p38 MAPK is a member of the MAPK family of kinases, which also includes ERKs and JNKs. It is a structurally conserved serine/threonine kinase characterized by a conserved kinase domain essential for enzymatic activity, along with regulatory regions that modulate its activation and substrate specificity (33). The kinase domain comprises a catalytic core that facilitates the transfer of phosphate moieties from adenosine triphosphate (ATP) to substrate proteins, a process known as phosphorylation.

The p38 MAPK family comprises four isoforms: p38α, p38β, p38γ, and p38δ, each encoded by a distinct gene and exhibiting unique tissue distribution, regulatory mechanisms, and functional roles (33). This classification helps understand how these isoforms contribute to the complexity of the p38 MAPK signaling pathway in health and disease (12,14). Among these, p38α is the most thoroughly characterized isoform and is ubiquitously expressed across almost all cell types, with predominant expression in the liver, heart, skeletal muscle, and brain, among others, where it is implicated in stress responses and apoptosis. By contrast, p38β is less understood but is hypothesized to have overlapping functions with p38α in certain contexts. p38γ is predominantly found in skeletal muscle, where it is hypothesized to facilitate muscle differentiation, while p38δ is primarily expressed in the brain and associated with neuronal signaling. Consequently, the differential activation of these isoforms leads to varied biological outcomes depending on the cellular context and specific stimuli involved. A summary of the four p38 MAPK isoforms, their tissue distribution, and their reported roles in the liver is provided in Table I.

Beyond its structural diversity, p38 MAPK is functionally classified into two primary cascades: The inflammatory and stress response routes. In the context of inflammation, p38 MAPK is triggered by cytokines, including interleukin-1 (IL)-1 and tumor necrosis factor (TNF)-α, thereby stimulating the subsequent synthesis of pro-inflammatory mediators and contributing to chronic inflammatory diseases. Conversely, exposure to environmental stressors, such as oxidative stress or UV radiation, may activate p38 MAPK, leading to cell cycle arrest or programmed cell death, underscoring its essential role in regulating cell fate (34).

The activation of p38 MAPK includes multiple upstream signaling pathways and stimuli which work together to activate the enzyme. The activation process begins with phosphorylation reactions that start when pro-inflammatory cytokines IL-1 and TNF engage their respective cell-surface receptors. The receptor-ligand binding process activates multiple signaling pathways, which produce downstream responses. These pathways activate MAPK kinase kinases (MKKKs), which then phosphorylate and activate particular MAPK kinases (MKKs), notably MKK3 and MKK6. These MKKs subsequently activate p38 MAPK through phosphorylation at both threonine and tyrosine sites located in the activation loop (4). The phosphorylation event triggers a structural transformation which enables p38 MAPK to phosphorylate its target proteins, including transcription factors and other kinases, thereby eliciting multiple cellular responses (12,14).

The activation of p38 MAPK occurs through two primary mechanisms: Cytokine release and oxidative stress. The cellular oxidative stress response produces reactive oxygen species (ROS), which activate p38 MAPK through multiple different pathways. It is critically implicated in the pathogenesis of diverse disorders, including neurodegenerative diseases and cancer, by regulating cellular viability and apoptotic processes (14).

The activation of p38 MAPK is influenced by multiple signaling pathways, which include NF-κB. The activation level of p38 MAPK and its downstream effects depend on interactions among these signaling pathways (12).

The body activates p38 MAPK when it detects environmental pollutants. Environmental plasticizers cause liver collagen buildup and elevated fibrosis indicators by activating the p38 MAPK/NF-κB signaling pathways. These findings underscore the pivotal role of p38 MAPK in driving environmental toxin-induced hepatic injury (14,25).

The p38 MAPK activation pathway is present in both disease states and normal bodily functions. The activation of p38 MAPK during stem cell differentiation enables it to control gene expression, which determines cell fate. Research has shown that p38 MAPK signaling is indispensable for driving osteogenic differentiation, as it enables mesenchymal stem cells to differentiate into osteoblasts during normal development (25). This hierarchical kinase cascade, from upstream MKKKs to the dual phosphorylation of p38 MAPK is delineated in Fig. 2, and the diverse downstream effectors that mediate its pleiotropic cellular functions are subsequently illustrated.

The p38 MAPK pathway elicits multiple effects that can result in protective or harmful responses, depending on the cell type and stimulus characteristics. The phosphorylation and subsequent activation of p38 MAPK trigger downstream effects that control inflammatory responses. In the context of liver fibrosis, p38 MAPK signaling increases the production of IL-6, TNF-α and IL-1β, thereby accelerating fibrosis progression (35).

The p38 MAPK signaling pathway is directly linked to apoptotic mechanisms. Phosphorylation of diverse downstream targets is triggered upon p38 MAPK activation. These substrates include pro-apoptotic factors such as BAD and caspases, which affect cell survival and apoptosis. Conversely, the p38 MAPK enzyme also protects cells from death by activating survival autophagy pathways during oxidative stress. The dual function of p38 MAPK yields a complex signaling molecule, as its output depends on both cellular conditions and the specific activation signals it receives (12).

In addition to its roles in inflammation and apoptosis, p38 MAPK participates in mechanisms that govern cellular differentiation. Research has shown that p38 MAPK signaling regulates the levels of essential transcription factors and osteogenic markers that guide osteogenic differentiation. Inhibition of p38 MAPK activity prevents mesenchymal stem cells from differentiating into osteoblasts, demonstrating that this pathway is essential for bone maintenance and repair (36). The regulatory function of p38 MAPK extends to multiple cell types, including immune cells, fibroblasts, and neurons, thereby affecting multiple biological processes and disease conditions (37,38).

The p38 MAPK pathway functions through numerous signaling pathways that activate NF-κB and ERK to control cellular responses. In inflammatory conditions, p38 MAPK can enhance NF-κB activation, leading to increased expression of inflammatory mediators. NF-κB controls p38 MAPK activity through a feedback loop that amplifies inflammatory responses. The p38 MAPK signaling pathway interacts with multiple pathways, demonstrating how cellular networks function as unified systems and creating opportunities for the development of specific medical interventions (14). The hierarchical activation of this pathway, from MKKKs to downstream effectors, is illustrated in Fig. 2.

The functional activity of HSCs fundamentally drives the progression of hepatic fibrosis. Studying this process requires understanding how p38 MAPK activation leads to HSC activation. The liver contains HSCs, which function as fat-storing cells, and Ito cells, which play essential roles in liver health and disease development. The body maintains HSCs in a resting state, which enables them to store vitamin A and preserve liver ECM stability. These cells remain inactive until liver damage or inflammation occurs, which triggers their activation into proliferative cells that display myofibroblast-like features. The liver then develops fibrosis through two main changes: Increased α-smooth muscle actin (α-SMA) protein expression and excessive production of ECM components, especially collagen in HSCs. This fibrous tissue accumulation can eventually progress to hepatic fibrosis and cirrhosis (4,7,20).

Research has shown that p38 MAPK signaling interacts with HSC activation in response to various stimuli, including cytokines and growth factors, to induce fibrogenic responses in HSCs. The activation of p38 MAPK is a critical step, as it triggers multiple cellular responses, including inflammation, apoptosis, and fibrosis, then regulates fibrogenic genes, including collagen- and α-SMA-encoding genes, which are essential for activated HSCs (73). Inhibiting this pathway was shown to reduce fibrogenic marker expression, collagen deposition, and HSC activation in experimental models (4,12,14).

The TGF-β signaling pathway is the primary mechanism that activates HSCs during the fibrogenic response to liver injury (74). Research has shown that activation of the p38 MAPK pathway increases TGF-β1 production (20,75,76). Elevated TGF-β1 levels activate p38 MAPK in HSCs, creating a feedback loop. This loop activates HSCs via TGF-β1 while strengthening p38 MAPK signaling, thereby increasing fibrotic tissue formation (4,77,78). Additionally, research has indicated that the p38 MAPK signaling cascade is indispensable for mediating TGF-β-induced activation of HSCs and for the fibrogenic response (76,79).

In addition to TGF-β1, other factors, such as ROS and inflammatory cytokines, can activate p38 MAPK in HSCs, thereby promoting fibrosis (12). Research has shown that high glucose levels in diabetes induce oxidative stress, which activates p38 MAPK, initiating HSC activation and fibrosis (80). The study demonstrates that p38 MAPK functions as a key regulator controlling HSC responses to various activation factors (80).

The process of HSC activation and proliferation is complicated by the interactions of p38 MAPK with several signaling pathways. The survival or death of HSCs depends on their signaling pathway interactions, which determine the extent of fibrosis development (81-83). As shown in Fig. 2, both TGF-β and oxidative stress converge on the p38 MAPK activation cascade, ultimately leading to the phosphorylation of key transcription factors, including myocyte enhancer factor 2 (MEF2) and activating transcription factor 2 (ATF2), which drive HSC transdifferentiation and fibrogenic gene expression (84,85).

Beyond initiating activation, p38 MAPK is a master regulator of the ECM remodeling that characterizes fibrosis. Notably, the p38 MAPK signaling pathway also contributes to enhanced stability of α1(I) collagen messenger RNA (mRNA) in HSCs, which in turn promotes the production and build-up of type I collagen (86). Supporting the clinical relevance of this pathway, simultaneous profiling of serum proteome and hepatic phosphoproteome in patients with metabolic dysfunction-associated steatohepatitis (MASH) revealed that liver p38 MAPK activation is independently associated with hepatic collagen deposition (11). Moreover, p38 MAPK signaling has been linked to the induction of other profibrotic factors, creating a feed-forward loop that exacerbates ECM remodeling in fibrotic tissues. It also regulates the activity of matrix metalloproteinases (MMPs), enzymes that degrade ECM components. Several studies performed in fibroblasts indicated that p38 MAPK and NF-κB signaling cascades are pivotal in driving the expression of MMPs, specifically MMP-13, MMP-3, and MMP-1 (87-89). The suppression of the p38 MAPK signaling cascade can markedly attenuate MMP-13 gene expression in rat HSCs, thereby preventing MMP-13 from degrading the ECM components, especially collagen (90). This dual role of p38 MAPK in promoting ECM deposition while also facilitating its degradation underscores its importance in maintaining ECM homeostasis. For example, in a study investigating hepatic alveolar echinococcosis, increased expression levels of p38 MAPK were associated with elevated TGF-β1 and bone morphogenetic protein-7 (BMP-7) in liver specimens from patients, indicating a strong association between p38 MAPK activation and ECM remodeling in liver fibrosis (4). Similarly, in models of chronic liver injury induced by carbon tetrachloride (CCl₄), p38 MAPK was activated, promoting the expression of ECM components and contributing to the progression of liver fibrosis (21).

Furthermore, p38 MAPK activity is not confined to HSCs. p38 MAPK is also a key signaling molecule that mediates the defenestration process of liver sinusoidal endothelial cells (LSECs) in response to increased matrix rigidity, thereby accelerating the advancement of hepatic fibrosis by regulating cytoskeletal reorganization (91). The activation of the focal adhesion kinase (FAK)-p38 MAPK signaling pathway in LSECs occurs when liver matrix stiffness increases, leading to their pathological defenestration (loss of fenestrae) (91). Stiff substrates promote FAK phosphorylation, which subsequently activates p38 MAPK and its downstream effector p38-mitogen-activated protein kinase-activated protein kinase 2 (MK2) (91). p38-MK2 activation results in LIM kinase 1 phosphorylation, ultimately inducing cofilin inactivation through its role as an actin depolymerization protein. The process results in increased actin polymerization, leading to stress fiber formation and reorganization of the actin cytoskeleton (91). These changes cause the collapse of fenestrae-associated cytoskeletal rings and LSEC defenestration, which represents the first stages of capillarization and fibrosis (91). The process is reversed when p38-MK2 signaling is blocked with SB203580, which restores fenestrae structures and LSEC phenotypic markers in fibrotic liver samples across different disease stages (91). Additionally, p38 MAPK functions as a primary mechano-transducer, causing LSEC dysfunction when cells experience stiffness (86). As illustrated in Fig. 1, p38 MAPK serves as a central node that integrates a range of profibrotic signals and transduces them into the key pathological outcomes of HSC activation and excessive ECM deposition.

The liver continues to sustain damage from ongoing inflammation and oxidative stress, which trigger hepatic fibrosis through multiple cellular and molecular mechanisms. The p38 MAPK pathway functions as a central signaling hub which combines inflammatory, oxidative, and apoptotic signals to control fibrotic disease progression.

Chronic liver injury is marked by increased concentrations of pro-inflammatory cytokines, including TGF-β, IL-1β, TNF-α, and IL-17A (4,92). Rather than being a passive responder, p38 MAPK activation serves as a critical amplifier within this inflammatory milieu. Upon stimulation by these cytokines, p38 MAPK enhances the inflammatory response through multiple mechanisms: It upregulates the expression of inflammatory enzymes such as cyclo-oxygenase-2, modulates MMP activity, and potentiates NF-κB signaling (4,93). This leads to sustained production of key pro-inflammatory mediators, which not only cause direct tissue damage but also create a microenvironment that perpetuates HSC activation and survival.

The role of p38 MAPK extends beyond cytokine signaling to direct mediation of inflammation-related cell death and environmental responses. For example, in DBP-induced liver fibrosis, p38 MAPK activation links inflammatory stimuli to hepatocyte pyroptosis, followed by HSC activation, directly tying inflammatory signaling to fibrotic tissue remodeling (14). Furthermore, p38 MAPK is implicated in the inflammatory aspects of MAFLD, contributing to insulin resistance and subsequent fibrogenic signaling (94). Other factors, such as LPS, exacerbate inflammation by promoting p38 MAPK-mediated degradation of autophagy-related proteins, including autophagy-related gene 13 (Atg13), in HSCs, thereby disrupting cellular homeostasis and favoring a pro-fibrotic state (95). The aging liver also exhibits a p38 MAPK-mediated inflammatory and mildly fibrotic phenotype, which can be modulated by interventions such as caloric restriction, highlighting the role of the pathway in environment- and age-dependent fibrogenesis (96). Thus, p38 MAPK is not merely activated by inflammation; it orchestrates a feed-forward loop that sustains and intensifies the profibrotic inflammatory response.

Oxidative stress is a hallmark of chronic liver injury and a potent activator of p38 MAPK (97). This relationship forms a critical, self-reinforcing axis in fibrosis. Signals from damaged hepatocytes, such as ROS directly activate p38 MAPK, which in turn increases the expression of inflammatory genes and genes associated with apoptosis, such as Bcl-2-associated X protein (Bax), alongside a reduction in the levels of the anti-apoptotic protein Bcl-2 (98). Notably, p38 MAPK activation can further stimulate ROS generation, establishing a self-amplifying cycle that intensifies oxidative damage and tissue injury (99).

This cyclical interplay has profound implications for liver fibrosis. In hepatocytes, activation of p38 MAPK triggered by oxidative stress promotes cell death and the release of inflammatory cytokines, which subsequently activate HSCs and drive fibrosis (7,100). Simultaneously, ROS can activate NF-κB, which enhances p38 MAPK pathway activity, leading to increased inflammation and sustaining a pro-fibrotic environment, linking hepatocyte injury to fibrogenic responses (101,102). This suggests that targeting oxidative stress and p38 MAPK activation may offer therapeutic avenues for mitigating liver fibrosis.

The dual nature of p38 MAPK in oxidative stress is context-dependent: While it can mediate protective responses by regulating antioxidant defenses such as glutathione and inhibiting expression of inducible nitric oxide synthase under specific conditions, its chronic activation under persistent oxidative stress typically leads to detrimental outcomes, including cell cycle disruption and apoptosis (27). This functional duality underscores that p38 MAPK can act as both a stress sensor and a determinant of cell fate, with its outcomes finely balanced by the cellular context and cross-talk with other pathways (103). Pharmacological inhibition of p38 MAPK has shown protective effects by bolstering cellular antioxidant systems, underscoring its pivotal role as both a mediator and a potential therapeutic breakpoint in the oxidative stress-fibrosis cycle (28). How pro-inflammatory mediators, specifically IL-1β and TNF-α, alongside oxidative stress, serve as key upstream activators of the p38 MAPK signaling cascade, highlighting the molecular basis for its central role in amplifying inflammatory and oxidative responses during liver injury is illustrated in Fig. 2.

The equilibrium between cell survival and apoptosis is critical in liver injury, as excessive hepatocyte apoptosis can lead to further fibrogenesis. Research has indicated that the activation of p38 MAPK can either facilitate or suppress apoptosis, contingent on the specific cellular environment and stimuli. The p38 MAPK pathway has been associated with the modulation of apoptosis across a range of cell types, including hepatocytes (14). Prolonged oxidative stress in hepatocytes activates p38 MAPK, leading to apoptosis via mitochondrial damage and caspase activation, thereby exacerbating liver damage (12,104). Research findings show that MASH develops in response to oxidative stress, which activates the MAPK phosphatase-1-p38 MAPK-liver kinase B1 nuclear signaling pathway. This pathway suppresses the enzymatic activity of the α catalytic subunit of adenosine 5'-monophosphate-activated protein kinase (AMPK), thereby triggering caspase-6 activation and culminating in cellular demise. The resulting inflammation drives liver fibrosis and MASH progression (105). The p38 MAPK pathway functions differently in HSCs because it generates survival signals that enable these cells to survive and build the ECM (14). However, p38 MAPK has been recognized as a crucial mediator of the apoptotic effect of Ocoxin on HSCs (106). IL-18 works together with Toll-like receptor 3 ligand stimulation to activate natural killer (NK) cells, enhancing their cytotoxic functions through the p38 MAPK/PI3K/Akt signaling pathway. These activated NK cells eliminate HSCs through TNF-related apoptosis-inducing ligand-mediated degranulation, thereby preventing fibrosis progression (107).

The body regulates p38 MAPK activity in a cell-type-specific manner, creating challenges for developing therapeutic strategies targeting this enzyme. p38 MAPK inhibition, as shown in animal studies of CCl₄-induced fibrosis, decreases collagen accumulation but may impair hepatocyte restoration processes (12,14). The downstream effectors shown in Fig. 2, including p53 and other pro-apoptotic factors, mediate the cell death-promoting functions of p38 MAPK in hepatocytes, whereas alternative signaling outputs may support survival in activated HSCs.

The development of hepatic fibrosis depends on multiple signaling pathways that interact through crosstalk mechanisms to regulate fibrogenesis. A comprehensive network map of these interactions is provided in Fig. 3, illustrating how p38 MAPK serves as a central signaling hub that both receives inputs from and coordinates outputs to multiple pro-fibrotic pathways. Rather than viewing each pathway in isolation, these interactions can be grouped into functional classes: i) Core pro-fibrotic feed-forward loops that drive disease progression; ii) metabolic and mechanosensitive signaling axes that link cellular stress to fibrogenesis; iii) counter-regulatory and pro-resolution pathways that oppose fibrosis; and iv) parallel MAPK cascades that collectively determine cell fate. The signaling pathways that drive hepatic fibrosis progression become less active when patients undergo lifestyle interventions that reduce liver inflammation and improve metabolic health, providing clinical evidence for the reversibility of these network interactions (108,109).

Among the pathways that intersect with p38 MAPK in liver fibrosis, TGF-β/Smad and NF-κB signaling form two interlocked feed-forward loops that are central to disease progression.

One of the most well-studied interactions involving p38 MAPK is its relationship with the TGF-β signaling cascade. The TGF-β1 signaling cascade is widely recognized as a principal mediator of hepatic fibrosis, promoting HSC activation and ECM deposition. Research has shown that TGF-β1 can initiate multiple downstream signaling cascades, including the Smad pathway, which is the main pathway of HSC activation and essential for mediating its fibrogenic effects (4,12). Additionally, TGF-β1 has been linked to the initiation of the p38 MAPK signaling cascade, which further amplifies the fibrogenic response by enhancing inflammation and apoptosis in hepatocytes (20). These findings indicate that the p38 MAPK pathway serves as an effector downstream of TGF-β signaling, mediating the fibrogenic effects of TGF-β1. For example, in a study investigating hepatic fibrosis, it was found that TGF-β1 induced the phosphorylation of p38 MAPK, which resulted in an upregulation of fibrogenic markers and an augmentation of collagen production, correlated with the severity of fibrosis in liver tissues (4). In another study, TGF-β was shown to stimulate CTGF expression, which in turn activated p38 MAPK, creating a feedback loop that exacerbated fibrosis (110). Upon receptor binding, TGF-β1 was demonstrated to activate Smad2 and Smad3, leading to their phosphorylation and nuclear translocation. This translocation was revealed to activate fibrogenic genes, including those encoding α-SMA and type I collagen (14,20). At the same time, TGF-β1 facilitated the production of sorting nexin protein-10 (SNX-10) through the p38 MAPK signaling cascade. In turn, SNX-10 modulated MMP9 release through direct protein-protein interactions, ultimately contributing to the progression of hepatic fibrosis (111). Furthermore, TGF-β1 stimulation triggered p38 MAPK activation, thereby enhancing MEF2C phosphorylation at the p38-specific residue, inducing activation of MEF2 and HSC (112). TGF-β1 also caused an increase in aerobic glycolysis in HSCs and stimulated the expression of glucose transporter 1 (GLUT1) in these cells via the stimulation of p38 MAPK, Smad, as well as PI3K/Akt signaling cascades. GLUT1 was shown to promote HSC glycolysis and activation (79). Research indicates that upregulation of integrin-β6 expression plays a pivotal role in the fibrogenic response associated with chronic cholestasis. p38 MAPK cascade facilitates TGF-β1-driven transcriptional upregulation of integrin-β6 mRNA within bile duct epithelial cells, specifically in MMNK-1 cell lines. This process is facilitated through the modulation of the activation of both activator protein 1 and Smad transcription factors (113). Notably, both p38 MAPK and Smad signaling pathways exert independent and additive effects on the transcriptional upregulation of the gene encoding type I collagen α1 chain. However, it is noteworthy that only p38 MAPK contributes to the enhancement of α1(I) collagen mRNA stability (71). Thus, feedback mechanisms characterize the relationship between p38 MAPK and TGF-β, as p38 MAPK activation can amplify TGF-β1 effects, thereby establishing a self-reinforcing cycle that intensifies fibrotic progression and leads to a vicious cycle of HSC activation and collagen deposition (114). Previous investigations have explored the potential of targeting the p38 MAPK pathway to mitigate TGF-β-induced fibrosis. Research involving liver fibrosis models has demonstrated that inhibiting p38 MAPK reduces TGF-β expression and its downstream effects, thereby ameliorating fibrosis (115-117).

The TGF-β/p38 MAPK loop is intimately coupled with NF-κB signaling. NF-κB functions as a transcription factor that regulates inflammatory responses and immune activation by controlling the expression of pro-inflammatory cytokine genes. The activation of p38 MAPK leads to the phosphorylation of inhibitor of κBα (IκBα), which removes its inhibitory function on NF-κB. The process enables NF-κB dimers to exit the cytoplasm and enter the nucleus, where they activate transcription of inflammatory cytokine genes, which in turn activate p38 MAPK (118). The two-way activation process between these cells creates a self-reinforcing cycle which results in continuous tissue damage and inflammation. Research has shown that p38 MAPK activation during the development of liver fibrosis leads to increased NF-κB signaling, resulting in higher production of the pro-fibrotic factors TGF-β and CTGF (119). This interplay is exemplified by the fact that inflammatory cytokines, such as TNF-α and IL-1β, can trigger p38 MAPK activation, which subsequently enhances TGF-β expression, perpetuating a cycle of inflammation and fibrosis (21).

The tight coupling of these two feed-forward loops may explain why single-target interventions often fail. Dual inhibition of TGF-β and NF-κB signaling, or direct targeting of their common downstream mediator p38 MAPK, has been proposed as a more effective strategy.

Moreover, the p38 MAPK and JAK/STAT signaling pathways also interact extensively during liver fibrosis. The activation of p38 MAPK leads to increased synthesis of TNF-α and IL-6, which not only feed back onto NF-κB but also activate the JAK/STAT pathway, thereby further enhancing inflammatory responses (120,121). The JAK/STAT signaling pathway is similarly activated after TGF-β1 cytokine binds to its receptor. The p38 MAPK and JAK/STAT pathways operate as a complex system that amplifies the inflammatory-fibrogenic network in the progression of liver fibrosis. This synergistic interaction creates a feed-forward loop that amplifies fibrogenic signaling, making co-targeting of these pathways an attractive therapeutic strategy (Fig. 3).

Beyond classical inflammatory and growth factor signals, metabolic and mechanical cues are integrated with p38 MAPK through the PI3K/Akt/mechanistic target of rapamycin (mTOR), YAP, and autophagy pathways and bile acids. The p38 MAPK and PI3K/Akt signaling cascades in liver fibrosis function together through coordinated activation, which strengthens their combined fibrotic effects. Research has indicated that the p38 MAPK signaling pathway interacts with the PI3K/Akt pathway, thereby protecting HSCs from apoptosis. It has been shown that blocking the PI3K/Akt signaling pathways renders p38 MAPK inhibitors more effective at inhibiting HSC activation driven by various p38 MAPK-dependent profibrotic mechanisms. Angiotensin II (AngII) increases the expression of essential proteins (PI3K, p-Akt, and p-P38 MAPK) in HSCs, thereby promoting fibrosis progression (12). The pathways show functional cross-talk because LY294002 treatment of PI3K and SB203580 treatment of p38 MAPK both block AngII-induced effects, including increased cell viability and migration, and elevated collagen I and α-SMA expression (12). HGF-overexpressed exosomes were shown to reduce both pathways, resulting in lower oxidative stress levels (NOX4 and malondialdehyde) and decreased p-p38 MAPK and PI3K/p-Akt activity in vivo, thereby treating CCl₄-induced liver fibrosis in mice (12). However, the context-dependent nature of this crosstalk is underscored by the finding that N-acetylglucosamine (GlcNAc)-carrying polymers, which mimic the multivalent GlcNAc moiety of O-linked β-GlcNAc-modified proteins, activate both p38 MAPK and PI3K/Akt signaling cascades in activated stellate cells. This activation produces anti-fibrotic effects by decreasing α-SMA expression and reducing collagen production (122). This seemingly paradoxical outcome underscores the context-dependent nature of p38 MAPK-PI3K/Akt crosstalk, where the net effect on fibrosis is dictated by factors such as activation kinetics, coincident signals, and downstream effector engagement. Moreover, it was demonstrated that PI3K-Akt-mTOR and p38 MAPK signaling cascades play a crucial role in the motility characteristics of HSCs. By contrast, the Smad-dependent TGF-β signaling cascade is primarily involved in their proliferation and contraction (123).

The metabolic stress connection is further strengthened by the p38 MAPK-YAP axis. Research has demonstrated that the activation of Hippo signaling transcriptional coactivator YAP1 in the context of MAFLD could be stimulated by the activation of p38 MAPK induced by free fatty acids (FFAs) (124). FFAs, which accumulate in hepatocytes during MAFLD, activate p38 MAPK (specifically the p38δ isoform MAPK13). This activation promotes the dephosphorylation/nuclear translocation of the transcriptional coactivator YAP. Once in the nucleus, the active form of YAP promotes transcription of profibrogenic target genes, including cysteine-rich protein 61, CTGF, ankyrin repeat domain 1, and ajuba homolog. The products of these genes stimulate HSC activation and subsequent ECM deposition, thereby driving the progression of liver fibrosis. Inhibition of p38 MAPK (via siRNA knockdown or chemical inhibitors such as SB203580) was shown to block FFA-induced YAP activation and its downstream fibrogenic effects. In addition, activation of HSCs by taurocholic acid was significantly associated with activation of the YAP signaling pathway, mediated by sphingosine 1-phosphate receptor 2 via the p38 MAPK pathway (125). The p38δ-YAP axis, shown in Fig. 3, represents a newly identified mechanism linking metabolic stress (FFAs) to fibrogenic gene expression, providing a rationale for targeting this specific isoform in MAFLD-associated fibrosis.

Autophagy adds another layer of metabolic regulation. The lysosomal degradation process of autophagy functions as a dual mechanism contributing to the progression of liver fibrosis. Basal autophagy plays a crucial role in maintaining cellular homeostasis. HSCs with impaired autophagic function may either survive longer and exacerbate fibrosis or undergo apoptosis, thereby mitigating fibrosis, depending on the specific context (126,127). The activation of p38 MAPK triggers the phosphorylation of the serine residue 757 within Unc-51-like autophagy activating kinase 1 (ULK1). This modification disrupts the ULK1-Atg13 complex, thereby blocking autophagic flux in activated HSCs via mTOR-dependent mechanisms, leading to increased collagen production and enhanced fibrogenesis (128). The p38 MAPK inhibitor SB203580 activates AMPK, thereby inducing autophagy, which strengthens the therapeutic effects of anti-fibrotic drugs (128). However, the natural compound harmine inhibits p38 MAPK and modulates AMPK/mTOR, relieving its suppression on the mTOR complex 1, reducing excessive autophagy in CCl₄-induced liver injury (129). This indicates that the outcome of p38 MAPK modulation of autophagy is highly dependent on the degree and context of pathway activation.

Bile acids further contribute to this metabolic signaling network. Research has focused on liver fibrogenesis by studying conjugated bile acids, specifically 12α-hydroxylated bile acids. Research has shown that liver tissue contains elevated bile acid levels of conjugated 12α-hydroxylated bile acids, which activate HSCs and promote liver fibrosis. Activation of the Takeda G-protein-coupled receptor, also known as G protein-coupled bile acid receptor 1, leads to phosphorylation-mediated upregulation of the p38 MAPK and ERK1/2 cascades (31). In a previous study, it was shown that metabolic factors, including bile acid buildup, affect fibrosis development by modulating essential signaling pathways. The study also demonstrated that modulation of bile acid signaling is a potential treatment approach (31). Collectively, the PI3K/Akt, YAP, autophagy, and bile acid pathways highlight the extensive integration of metabolic and mechanical signals at the p38 MAPK node, although the context-dependent effects, which are sometimes pro-fibrotic, sometimes anti-fibrotic, call for careful evaluation of isoform-specific and cell-type-specific therapeutic strategies.

In contrast to the pro-fibrotic circuits previously described, BMP-7 and the reversal of EMT represent endogenous counter-regulatory mechanisms that converge on p38 MAPK. BMP-7 functions as an essential factor that inhibits hepatic fibrosis. The compound blocks the fibrogenic effects of TGF-β1, induces HSC apoptosis, and reduces their collagen-producing capacity. The maintenance of liver homeostasis depends on the proper balance between TGF-β1 and BMP-7 signaling pathways. The body develops excessive fibrosis when its fibrosis regulation system becomes unbalanced. Research has shown that BMP-7 acts as a protective factor through its ability to stop TGF-β1 from activating the p38 MAPK pathway, which prevents fibrogenesis (4). HSC activation depends on EMT, and the MET of HSCs helps resolve fibrosis. A decrease in the TGF-β1:BMP-7 ratio was shown to lead to reduced levels of total and phosphorylated p38 MAPK, allowing cells to revert from EMT to MET. The transition became apparent through the loss of EMT markers, including α-SMA and desmin, while MET marker and E-cadherin reappeared (130). As shown in Fig. 3, BMP-7 counteracts TGF-β1 signaling by suppressing p38 MAPK activation, representing a natural counter-regulatory mechanism that could be harnessed therapeutically to promote fibrosis resolution. The development of pharmacological agents which activate BMP-7 signaling and block TGF-β1 and p38 MAPK activation pathways shows promise for treating and stopping fibrosis progression (7).

p38 MAPK also interacts with other MAPK signaling cascades, such as JNKs and ERKs. The p38 MAPK, JNK, and ERK pathways work together to regulate essential processes in liver fibrosis by modulating HSC activation, inflammation, apoptosis, and ECM deposition.

The JNK signaling pathway is essential for regulating both cell death and cell growth. The process is activated when cells face stress and inflammatory signals emerge, leading to liver fibrosis through hepatocyte apoptosis and an increased inflammatory response. JNK activation leads to c-Jun phosphorylation. c-Jun is a crucial transcription factor that regulates the expression of survival- and apoptosis-related genes (131). The activation of p38 MAPK and JNK pathways is of particular interest because they respond to identical triggers, producing a synchronized cellular response that determines cell survival or death based on activation timing and environment.

By contrast, the ERK signaling pathway primarily promotes cell proliferation and differentiation by being activated by growth factors and mitogens. The activity of p38 MAPK and JNK depends on ERK, which regulates their downstream effects. Research shows that the ERK and p38 MAPK pathways function together to regulate cell-cycle events and stress responses in polyploid, giant cancer cells, suggesting that HSCs employ similar mechanisms to develop fibrotic tissue (131).

The outcome of fibrosis results from the interaction between these two pathways. The activation of ERK promotes cell survival and proliferation, whereas persistent JNK/p38 MAPK signaling pathways lead to apoptosis and inflammation (132,133). In liver fibrosis, oxidative stress and cytokine release of TNF-α and IL-6 may activate all three MAPK signaling pathways, creating a sustained cycle of HSC activation and ECM deposition (134). The p38 MAPK and ERK pathways serve as targets for inhibition because this approach would break the self-sustaining cycle (135). The complex interplay among the p38 MAPK, JNK, and ERK pathways, which collectively determine cell-fate decisions ranging from proliferation to apoptosis in the context of liver fibrosis is shown in Fig. 3.

The inflammatory response is another critical component of hepatic fibrosis, and inflammatory signaling pathways often intersect with pathways involved in fibrogenesis. The p38 MAPK signaling cascade is activated through elevated levels of the pro-inflammatory mediators TNF-α and IL-6, resulting in a marked augmentation of fibrogenic response. HSC activation decreases when anti-inflammatory signals enter the system because these signals promote HSC death (136). The regulatory mechanisms of hepatic fibrosis become complex because pro-inflammatory and anti-inflammatory signals interact with each other and with p38 MAPK and other essential pathways. Collectively, the signaling network depicted in Fig. 3 establishes p38 MAPK as a central hub that integrates a range of fibrotic inputs and coordinates multi-pathway outputs. The most biologically significant mechanisms, the interlocked TGF-β/NF-κB/p38 feed-forward loops and the metabolic-mechanical axes converging on p38 MAPK, represent priority targets for therapeutic intervention. The complexity and context dependence of these interactions underscore the rationale for simultaneously targeting multiple nodes, or its downstream effectors within the network, in combination therapies for liver fibrosis. p38 MAPK interactions with key signaling pathways in liver fibrosis are summarized in Table III.

Research has focused on studying how miRNAs interact with the p38 MAPK pathway to understand cellular processes that include inflammation, fibrosis, and cancer development. Non-coding RNAs, such as miRNAs, regulate gene expression post-transcriptionally as short molecules, influencing biological processes such as cell proliferation, differentiation, and apoptosis. The interaction between miRNAs and p38 MAPK depends on multiple factors, which include the cellular context and the specific miRNAs involved (137).

A previous study showed that specific miRNAs directly bind to components of the p38 MAPK pathway, thereby modulating their activity. It also demonstrated that miRNAs serve as vital regulators of the p38 MAPK pathway, which controls cellular responses to external stimuli. The study revealed that miR-146b-3p reduces p38 MAPK signaling in monocytes, thereby altering their inflammatory response (138). Notably, miRNAs can act as crucial upstream regulators of the pathway. For example, research in Caenorhabditis elegans has shown that elevated intestinal expression of miR-794 modulates the response to nanoplastic toxicity by affecting downstream transcription factors in both p38 MAPK- and insulin-mediated signaling cascades (139). Furthermore, in human immune cells, treatment with inactivated probiotic strains can significantly downregulate p38 MAPK expression while concurrently altering the levels of immune-related miRNAs such as miR-146a and miR-155, providing direct evidence of miRNA-p38 MAPK interplay in immune regulation (137).

The p38 MAPK pathway interacts with miRNAs through multiple mechanisms which go beyond direct miRNA targeting. It is also mediated by various signaling cascades involving other pathways. Activation of the p38 MAPK pathway by miR-802 leads to oxidative stress and regulation of insulin resistance in liver fibrosis, according to research (140). Another study found that oxidative stress reduced miR-144 levels, leading to decreased expression of the SIN3 transcription regulator family member A (SIN3A). The study demonstrated that activation of the p38 MAPK signaling pathway was mediated by SIN3A downregulation, leading to HSC activation and worsening liver fibrosis (141). The study showed that miRNAs regulate p38 MAPK activity by modulating signaling networks that activate it. This regulation can be part of a complex network. For example, in lead-induced neurotoxicity, a regulatory network involving a long non-coding RNA (lncRpa), a circular RNA (circRar1), and miR-671 was shown to cooperatively promote the upregulation of apoptosis-associated genes, including p38, revealing a significant role for non-coding RNA networks in controlling p38 MAPK expression (142).

Research has shown that miRNA-p38 MAPK interactions hold therapeutic potential, as specific miRNA inhibitors and mimics can affect diseases resulting from p38 MAPK dysfunction. Such findings suggest that targeting miRNAs that regulate p38 MAPK could provide novel therapeutic avenues for treating conditions associated with chronic inflammation and fibrosis. Additionally, in the context of viral infections such as COVID-19, virus-induced immune-epigenetic reprogramming may affect MAPK signaling, suggesting that targeting the relevant miRNA-p38 MAPK axis could be a strategy to modulate dysregulated immune responses, such as macrophage activation syndrome (143). Furthermore, under other stress conditions, such as viral infection and cardiovascular dysfunction, the expression of transcription factors such as nuclear factor of activated T cells 5, which interacts with the p38 MAPK pathway, is also regulated by miRNAs and epigenetic modifications, expanding the significance of the miRNA-p38 MAPK regulatory network in disease (144).

One of the most significant controversies concerns the dual role of p38 MAPK in cell survival and death. Research has shown that p38 MAPK activation can either promote or suppress apoptosis depending on the cellular context. For example, fibulin-1 was shown to promote HSC activation via the p38 MAPK pathway, suggesting a pro-survival, pro-fibrogenic role in these cells (198). Conversely, in cardiomyocytes, upregulation of dual specificity protein phosphatase 4 was found to mitigate doxorubicin-induced cardiotoxicity by inhibiting the p38 MAPK/MK2 signaling axis, thereby underscoring the protective effect of p38 inhibition in parenchymal cells (199). In hepatocytes exposed to toxic agents, p38 MAPK activation under oxidative stress was demonstrated to lead to cell death, while in activated HSCs, it promoted survival and fibrogenic activity (14). The differential engagement of downstream substrates, such as p53 and Bax in hepatocytes vs. survival factors in HSCs, may explain these opposing outcomes (200-202). These opposing outcomes can be reconciled by conceptualizing p38 MAPK as a 'context-dependent rheostat': In mesenchymal cells such as HSCs and osteoblasts, its activation supports survival and differentiation, whereas in parenchymal cells such as hepatocytes and cardiomyocytes, it predominantly mediates stress-induced apoptosis (203,204). This cell-type-specific duality highlights that therapeutic targeting must consider not only the kinase itself but also the cell-type-specific downstream effector landscape. Given this duality, systemic p38 MAPK inhibitors are unlikely to succeed in liver fibrosis; instead, cell-type-specific delivery strategies (such as HSC-targeting nanoparticles) or isoform-selective inhibitors that spare hepatocyte p38α should be prioritized.

Further complicating the picture, p38 MAPK appears to exert stage-dependent effects during HSC activation. Research has demonstrated that blocking p38 MAPK during the early stages of HSC activation reduces α-SMA expression, whereas inhibiting this kinase in already-activated HSCs fails to produce similar effects. Moreover, p38 suppression in activated HSCs paradoxically increased cell proliferation, suggesting that p38 MAPK may exert anti-proliferative functions once HSCs have fully transdifferentiated (85). These stage-dependent effects can be conceptualized through a 'temporal switch' model: In early HSC activation or acute inflammation, p38 MAPK drives a pro-fibrogenic and pro-inflammatory program, whereas in established disease, its sustained activation may shift toward growth-suppressive or tissue-remodeling functions. This implies that the therapeutic window for p38 MAPK inhibitors may be limited to early fibrotic stages, with potential risks if administered during established disease.

Emerging evidence suggests that targeting regulators upstream of p38 MAPK activation, rather than the kinase itself, may offer a more precise therapeutic window. In MASH, ubiquilin 1 (UBQLN1) was found to initiate the p38 MAPK pathway by mediating the degradation of its suppressor, suppressor of IKKε (SIKE). Inhibition of this UBQLN1-SIKE-p38 MAPK axis mitigated hepatic steatosis and fibrosis (196). This indicates that the pathological activation of p38 MAPK is tightly controlled by specific upstream modulators, and interventions at this level could be more effective and potentially stage-specific than direct kinase inhibition.

p38 MAPK also displays opposing functions in ECM turnover. While it promotes ECM deposition by stabilizing collagen mRNA (86), it can also induce MMPs, including MMP-1, MMP-3, and MMP-13 (87-89). In intervertebral disc degeneration, baicalin exerted protective effects by suppressing the p38 MAPK signaling cascade, leading to downregulation of catabolic factors such as MMP-3 and MMP-13 (205). Conversely, its well-established role in driving the synthesis of pro-inflammatory cytokines, specifically IL-6, IL-1β, and TNF-α, has been confirmed in models of shoulder adhesive capsulitis and gastric ulcers, where p38 inhibition reduced inflammation and tissue fibrosis (197,206). Similarly, in the context of inflammation, p38 MAPK acts primarily as a pro-inflammatory mediator, yet it can also participate in protective antioxidant responses under certain conditions, such as genistein-mediated cardioprotection (27). This functional dichotomy can be understood through a 'temporal-spatial switch' model: In early acute responses, p38 MAPK drives pro-inflammatory cytokine synthesis and ECM remodeling, whereas in chronic settings, its sustained activation may shift toward catabolic MMP expression (such as MMP-3 and MMP-13) or tissue degradation. The net effect, pro-fibrotic or fibrolytic, is dictated by the balance between these outputs, which in turn depends on cell type, disease stage, and the duration of pathway engagement (103).

The relationship between p38 MAPK and cellular degradation pathways extends beyond classical apoptosis to include autophagy and ferroptosis. Research indicates that inhibiting p38 MAPK with SB203580 restores the autophagic flux by blocking the inhibitory phosphorylation of p38 on ULK1 (128). Conversely, the natural compound harmine was shown to reduce excessive autophagy in CCl₄-induced liver injury by inhibiting p38 MAPK and modulating AMPK/mTOR signaling (129). In acute kidney injury induced by depleted uranium, downregulation of ethylmalonic encephalopathy 1 led to ROS-mediated activation of the p38 MAPK pathway, which subsequently promoted nuclear receptor coactivator 4-mediated ferritinophagy, ultimately triggering renal cell ferroptosis (207). In neutrophils, constitutive p38 MAPK phosphorylation was found to be involved in spontaneous apoptosis, as SB203580 and antisense oligonucleotides delayed apoptosis by ~24 h (208). These findings indicate that p38 MAPK serves as a 'stress-responsive hub' that integrates signals toward apoptosis, autophagy, or ferroptosis depending on the cellular context and upstream stimuli. For instance, in renal cells, p38 activation has been shown to lead to ferroptotic cell death, while in neutrophils, it has been found to promote spontaneous apoptosis as a physiological clearance mechanism (207,209). The final outcome is determined by the balance of ROS, AMPK/mTOR status, and the availability of iron-dependent pathways.

The clinical translation of p38 MAPK inhibitors continues to face significant hurdles, primarily owing to adverse toxic effects and insufficient therapeutic benefit in complex diseases (210). While preclinical studies demonstrate promising anti-fibrotic efficacy, clinical trials in other inflammatory diseases have revealed issues with dose-dependent toxicity, off-target effects, and tachyphylaxis, where initial anti-inflammatory effects wane over time (190,191). For example, in COPD, losmapimod failed to improve exercise tolerance despite good tolerability (187). In atherosclerosis, BIRB 796 (doramapimod) and BMS-582949 did not reduce arterial inflammation vs. placebo (188). These failures suggest that p38 MAPK inhibition alone may be insufficient and may require combination strategies (189). Moreover, the lack of isoform selectivity in early inhibitors likely contributed to adverse effects by disrupting physiological p38 MAPK functions in non-target tissues (184,185). These divergent therapeutic outcomes between p38α-specific inhibitors and dual p38α/β inhibitors in conditions such as cancer-associated cachexia further underscore the need for isoform-selective approaches (186).

To overcome current challenges, several strategies should be prioritized. Recognizing that direct p38 MAPK inhibition has faced clinical hurdles due to tachyphylaxis and toxicity, a shift toward more upstream or downstream nodes within the pathway is warranted. First, targeting downstream effectors such as MK2 may offer sustained anti-inflammatory effects without the tachyphylaxis observed with direct p38 MAPK inhibitors (191). Furthermore, exploiting upstream regulators, such as the UBQLN1-SIKE axis, or inducing inhibitory post-translational modifications, offers novel avenues for precise intervention that may avoid the toxicity associated with direct kinase inhibition. This upstream-downstream dichotomy can be framed as a 'hierarchical targeting strategy': Intervening at the level of a single, context-specific upstream regulator may yield more selective effects than blocking the pleiotropic p38 MAPK kinase itself, and targeting a downstream effector could circumvent compensatory feedback loops that cause tachyphylaxis.

Second, cell-type-specific targeting is being explored. For example, the myeloid-specific p38α inhibitor MPL-5821 was shown to potently augment the inflammatory and phagocytic responses of human macrophages against Staphylococcus aureus without causing systemic toxicity, thereby presenting a novel antibacterial approach (211). Hence isoform- and cell-type-selective inhibitors, such as MPL-5821, for specific cell populations (for example, myeloid cells) can minimize on-target, off-tissue effects (196,211,212). The distinct tissue distribution and functional roles of p38α, p38β, p38γ, and p38δ make isoform-selective inhibitors a promising avenue, particularly for p38δ, in MAFLD-associated fibrosis (33,124,125). This approach is supported by evidence that while p38α is ubiquitously expressed and drives canonical inflammatory responses, p38δ is enriched in myeloid and hepatic cells and is linked to steatohepatitis and fibrosis. Thus, isoform selectivity offers a 'cellular precision' strategy that could preserve the protective functions of other p38 isoforms in non-target tissues.

Third, the success of combination regimens in SMA models should be rigorously tested in fibrotic diseases, potentially pairing p38 pathway modulators with anti-fibrotic, anti-inflammatory, or metabolic agents (213). In spinal muscular atrophy (SMA), pharmacological inhibition of p38 MAPK synergized with survival motor neuron-upregulating drugs, enhancing motor neuron survival and synaptic rewiring, demonstrating a powerful combinatorial neuroprotective strategy (213). Given the extensive crosstalk illustrated in Fig. 3, co-targeting p38 MAPK with TGF-β/Smad, NF-κB, or PI3K/Akt may yield synergistic effects while allowing lower doses of individual agents, thereby minimizing toxicity (14,20). This combination approach is conceptually supported by the observation that p38 MAPK functions not in isolation but as a 'signaling hub' that integrates with the MAPK family (ERK and JNK) and the TGF-β1 pathway to drive HSC activation and ECM remodeling (106,214). A rational combination, for instance, pairing a p38 inhibitor with a TGF-β receptor kinase inhibitor, could disrupt both the initiation and the maintenance phases of fibrosis. Fourth, elucidating the precise molecular determinants that dictate the pro-fibrotic vs. the protective outcomes of p38 MAPK, whether they are post-translational modifica- tions, interacting partners, or spatial signaling dynamics, will be essential for developing context-aware therapeutics. Emerging technologies, including single-cell transcriptomics and spatial proteomics, offer powerful tools to dissect p38 MAPK signaling heterogeneity across hepatic cell populations during fibrosis progression and regression.

Fifth, novel approaches to target the pathway are being discovered. A vitamin C-based nanostructure was found to inhibit hepatic stellate cell proliferation and fibrosis by covalently modifying p38 MAPK (vitcylation), blocking its nuclear translocation and inducing cell cycle arrest (212). This represents a move beyond traditional ATP-competitive inhibitors and potentially enabling context-specific modulation.

In summary, the contradictions in the p38 MAPK literature do not diminish its importance as a therapeutic target but rather underscore the need for more nuanced approaches. The apparent contradictions in cell survival, ECM turnover, and autophagy regulation can be reconciled by viewing p38 MAPK as a 'context-dependent signaling rheostat,' where its output is determined by a 'temporal-spatial switch' (pro-fibrotic early, anti-proliferative late) and a 'bidirectional modulator' of autophagy and cell death pathways (175,177,215). Previous studies reinforce p38 MAPK as a master regulator in fibrosis and related pathologies within a highly contextual signaling network (124,216-219). The apparent contradictions highlight its pleiotropic functions rather than invalidating it as a target. The future lies in developing sophisticated intervention strategies that account for cellular context, disease stage, and pathway crosstalk to harness their therapeutic potential safely. Moving forward, the field must prioritize isoform-specific targeting, stage-dependent interventions, and rational combination regimens to translate the promise of p38 MAPK modulation into effective clinical treatments for patients with progressive liver fibrosis.