FSTL1 regulates cellular proliferation through complex mechanisms that vary across different cell types. This regulatory activity is particularly evident in tumour cell lines (24,25). For example, in MDA-MB-231 breast cancer cells, FSTL1 acts as a cell proliferation inhibitor, whereas in gastric cancer cells, it promotes cellular proliferation (26,27). This cell type-specific regulation highlights the functional diversity of FSTL1.

The role of FSTL1 in inflammatory responses is multifaceted, involving complex and precisely coordinated mechanisms (28,29). In terms of immune cell regulation, FSTL1 modulates immune cell infiltration and activation, maintaining immune system homeostasis by balancing pro-inflammatory and anti-inflammatory responses (27,30,31). By inhibiting hyperactivation of neutrophils and macrophages, FSTL1 helps prevent sustained inflammatory damage (31,32).

Inflammatory signal transduction is central to the regulatory functions of FSTL1. By modulating pathways such as NF-κB and MAPK, FSTL1 is involved in both the initiation and resolution of inflammation, serving a key role in innate and adaptive immune responses (33,34). Notably, FSTL1 interacts with the Toll-like receptor (TLR) system, particularly TLR4, to orchestrate inflammatory processes (Fig. 1). Through TLR4 engagement, FSTL1 activates the MyD88-dependent signalling cascade, triggering the downstream activation of NF-κB and MAPK pathways, which regulate the production of pro-inflammatory cytokines and chemokines across various cell types (2,35). The TLR4/MyD88/NF-κB axis represents a critical mechanism by which FSTL1 fine-tunes inflammatory responses in both physiological and pathological contexts. In certain scenarios, FSTL1 also exhibits anti-inflammatory properties by inhibiting TLR4-mediated inflammatory signalling, highlighting its context-dependent immunomodulatory functions. These unique regulatory mechanisms enable FSTL1 to orchestrate immune network interactions, serving an essential role in maintaining immune balance (30).

FSTL1 is a key regulator in cartilage biology, influencing chondrocyte behaviour and tissue homeostasis (7,36,37). In chondrocyte metabolism, FSTL1 promotes chondrocyte proliferation and differentiation, regulates cartilage matrix synthesis, and participates in complex cartilage tissue remodelling processes (38-40), all of which are essential for maintaining cartilage integrity and biomechanical function.

Emerging evidence has highlighted the specific pathological mechanisms of FSTL1 in joint disorders (41,42). In conditions such as osteoarthritis, FSTL1 contributes to disease onset and progression by modulating inflammatory responses, influencing chondrocyte apoptosis and survival, and regulating cartilage matrix protein expression through the TGF-β signalling pathway (2,43,44). Cartilage development and regeneration represent critical areas of FSTL1 research, given its potential in regulating cartilage-specific transcription factors, and promoting cartilage regeneration and repair (45,46).

FSTL1 regulates TGF-β superfamily signalling through intricate molecular mechanisms, serving a central role in cellular biological processes (Fig. 1). The TGF-β pathway is essential for regulating cell proliferation, differentiation, migration and tissue development, with FSTL1 acting as a precise modulator in this context (47,48). Previous studies have established FSTL1 as a TGF-β-inducible gene encoding a secreted glycoprotein, creating a bidirectional regulatory relationship between FSTL1 and TGF-β signalling (44,49).

During mesenchymal cell development and tissue remodelling, FSTL1 influences TGF-β signal transduction through multiple mechanisms (39). One key mechanism involves the direct regulation of Smad protein phosphorylation, which impacts cell fate decisions (41). In 2025, research demonstrated that FSTL1 accelerates cellular apoptosis and extracellular matrix degeneration by activating the TGF-β/Smad2/3 pathway, promoting dose-dependent increases in phosphorylated (p)-Smad2/Smad2 and p-Smad3/Smad3 ratios, leading to nuclear translocation of these transcription factors (44). In processes such as cardiac regeneration, FSTL1 stimulates cardiomyocyte proliferation and differentiation via the TGF-β/Smad pathway, thereby facilitating tissue repair and functional recovery (44,50). FSTL1 enhances TGF-β non-Smad signalling by promoting phosphorylation-driven activation of the Raf/MEK/ERK cascade, thereby amplifying associated fibrogenic and proliferative effects (51). Moreover, exercise-induced FSTL1 has been shown to promote cardiac angiogenesis through the disco-interacting protein 2 homolog A (DIP2A)-Smad2/3 pathway following myocardial infarction, highlighting its therapeutic potential in cardiovascular regeneration (21,52-55).

FSTL1 regulates the TGF-β pathway at multiple molecular levels (56,57). In this context, FSTL1 modulates the phosphorylation levels of Smad2/3 proteins, alters their binding affinity with receptor complexes, and influences their nuclear translocation and transcriptional activity (40). A 2025 study confirmed the direct regulatory relationship between FSTL1 and TGF-β/Smad signalling, showing that TGF-β pathway inhibition using SB-431542 may reverse FSTL1-induced Smad2 and Smad3 phosphorylation (44). Additionally, FSTL1 regulates the spatial configuration of type I and II TGF-β receptors, affecting the stability of their interactions and modulating signal transduction efficiency (58).

In inflammatory microenvironments, FSTL1 expression is modulated by inflammatory cytokines such as TGF-β1, IL-1β and TNF-α (52,59). Its expression is subject to dose- and time-dependent regulation. Recent findings have suggested that plasma FSTL1 levels can serve as a non-invasive diagnostic biomarker for inflammatory and fibrotic diseases (60,61). By controlling the release of inflammatory mediators and modulating immune cell infiltration and activation, FSTL1 helps maintain inflammatory homeostasis (31,32).

FSTL1 and TGF-β signalling form a bidirectional regulatory network that is essential for tissue homeostasis and remodelling (52,62,63). FSTL1, as a TGF-β-inducible gene, is upregulated by TGF-β1 through Smad3-dependent transcriptional activation. In turn, secreted FSTL1 functions as a matricellular protein that facilitates TGF-β receptor complex formation and amplifies downstream signalling, creating a positive feedback loop. At the molecular level, FSTL1 directly regulates Smad2/3 phosphorylation, nuclear translocation and transcriptional activity, with TGF-β inhibitors reversing FSTL1-induced Smad phosphorylation (44,57,63). This TGF-β/Smad-FSTL1 axis orchestrates various physiological processes, including mesenchymal cell differentiation, extracellular matrix synthesis, cardiac regeneration and fibrotic responses (63,64). In inflammatory microenvironments, FSTL1 expression is modulated by cytokines such as TGF-β1, IL-1β and TNF-α (52,62,63). These multifaceted mechanisms position FSTL1 as a key amplifier in TGF-β-mediated signalling networks.

The NF-κB signalling pathway is a key regulator of cellular inflammation and immune responses (Fig. 1), with a critical role in inflammatory diseases, immune modulation and cell survival (65,66).

FSTL1 interacts with the NF-κB pathway in a bidirectional, context-dependent manner, with effects varying across tissue types and disease models. Recent studies have shown that in kidney inflammation, FSTL1 derived from renal tubular epithelial cells inhibits NF-κB activation, protecting against kidney fibrosis by reducing renal epithelial inflammation (67,68). Mechanistically, FSTL1 suppresses TNF-α-induced phosphorylation and nuclear translocation of NF-κB p65, thereby decreasing IL-1β, IL-6 and ICAM-1 expression, and limiting leukocyte infiltration (67,68). By contrast, in pulmonary fibrosis, FSTL1 promotes NF-κB activation, driving epithelial-mesenchymal transition and inflammation. FSTL1 expression is induced by TGF-β1, leading to NF-κB phosphorylation and establishing a pro-fibrotic feedback loop. Quercetin alleviates pulmonary fibrosis by downregulating FSTL1 expression and modulating NF-κB signalling (68).

FSTL1 is also essential for the initial activation of NF-κB signalling in specific disease contexts (31,35). By regulating the activity of the IκB kinase complex, FSTL1 directly affects the phosphorylation and degradation of NF-κB (31,35,69). In neuroinflammatory models, FSTL1 knockdown reduces microglial activation by suppressing NF-κB signalling, thereby protecting against neurological damage in Parkinson's disease models (70). In nucleus pulposus cells, FSTL1 accelerates cellular senescence and intervertebral disc degeneration (IVDD) through TLR4/NF-κB pathway activation (2). In macrophages and other immune cells, FSTL1 regulates NF-κB nuclear translocation and transcriptional activity, influencing the expression and release of inflammatory cytokines to maintain inflammatory homeostasis (35).

Oxidative stress is a key trigger for the activation of the NF-κB signalling pathway, with FSTL1 exerting complex regulatory effects on intracellular reactive oxygen species (ROS) production. In high glucose-induced oxidative stress models, FSTL1 exacerbates oxidative stress and cellular transdifferentiation injury in renal tubular epithelial cells, thereby promoting NF-κB activation and subsequent inflammatory responses (71).

Regulating inflammatory cytokine expression is a central mechanism through which FSTL1 modulates the NF-κB pathway (31,72). FSTL1 precisely controls the expression of inflammatory cytokines such as TNF-α, IL-6 and IL-1β, with its regulatory direction being tissue-specific: In renal epithelial cells, FSTL1 upregulation decreases TNF-α-induced secretion of IL-1β and IL-6 through NF-κB inhibition (67), whereas in pulmonary epithelial cells, FSTL1 enhances the secretion of these cytokines via NF-κB activation (2). Bioinformatics analyses have confirmed notable positive associations between FSTL1 and key NF-κB pathway components (RELA and NFKB1), as well as downstream cytokines, in patients with pulmonary fibrosis (68). In various inflammatory disease models, FSTL1 demonstrates marked anti-inflammatory effects by inhibiting NF-κB signalling, thereby reducing the intensity and duration of inflammatory responses (31,73).

Cell apoptosis and survival, central to NF-κB regulation, are also influenced by FSTL1, which impacts cell survival decisions through NF-κB-mediated modulation of apoptosis-related proteins and anti-apoptotic factors (74,75). In neurodegenerative disease models, particularly Parkinson's disease, inhibition of HOXA11-AS protects mice from neuroinflammation and neuronal apoptosis through the microRNA-124-3p-FSTL1-NF-κB axis, illustrating the therapeutic potential of targeting FSTL1-NF-κB signalling (70). In autoimmune disease models, FSTL1 has emerged as both a potential therapeutic target and a biomarker of inflammation, with its expression associated with disease activity in rheumatic diseases (74,76,77).

The regulation of the NF-κB pathway by FSTL1 is tissue- and disease-specific (27,78), with its regulatory patterns varying across cell types and disease models. In neuroinflammation, it may exert notable inhibitory effects, whereas in tumour microenvironments, the regulatory mechanisms are more complex (75,79). Specifically, in tumours, FSTL1 modulates tumour progression and metastasis by regulating the inflammatory polarisation of tumour-associated macrophages, offering potential targets for tumour immunotherapy (78,79).

FSTL1 regulates a wide range of biological processes, including cellular stress responses, proliferation, survival and inflammation, primarily through the MAPK signalling pathway (Fig. 1) (17,80). Recent research has revealed that FSTL1 can function as both an activator and an antagonist of MAPK signalling, with its effects dependent on the cellular context (81).

Regulation of the MAPK pathway by FSTL1 is highly cell- and tissue-specific, and its mechanisms vary across different tumour cell types. In 2024, pioneering research demonstrated that FSTL1 acts as an antagonist of ERK1/2 phosphorylation during ciliogenesis and preadipocyte differentiation, revealing an inhibitory role in MAPK signalling that contrasts with its activating effects in other contexts (81). In the breast cancer cell line MDA-MB-231 and in cervical cancer cells, FSTL1 inhibits cell proliferation by regulating the phosphorylation and activity of MAPK family members, such as ERK, JNK and p38, thus influencing downstream gene expression and cell fate (82,83). In cervical cancer, FSTL1 upregulation markedly reduces cell proliferation, migration and invasion, while promoting apoptosis through downregulation of the insulin-like growth factor 1 receptor/PI3K/AKT pathway, which intersects with MAPK signalling.

FSTL1 serves a central role in regulating the inflammatory response, primarily mediating inflammatory cascades through the MAPK and NF-κB pathways. In cardiac fibrosis models, FSTL1 promotes profibrotic mechanisms by activating MAPK signalling via TGF-β1. FSTL1 upregulation enhances TGF-β signalling, leading to increased activation of ERK, JNK and p38 pathways. By contrast, depletion of FSTL1 reduces the levels of ERK, JNK and p38, while blocking JNK and p38 markedly impairs fibroblast proliferation, differentiation and migration (84). Furthermore, glycosylated FSTL1 specifically induces cardiac fibroblast proliferation through ERK1/2 activation, whereas non-glycosylated FSTL1 may exert distinct effects (85-87).

FSTL1-induced regulation of inflammation exhibits notable heterogeneity across different tissues (37). In nucleus pulposus cells and in IVDD, FSTL1 accelerates cell senescence and promotes inflammation via TLR4/NF-κB pathway activation, rather than directly through MAPK signalling. FSTL1 expression is upregulated in degenerative disc tissues, and FSTL1 small interfering RNA (siRNA) notably inhibits IVDD progression by reducing inflammatory responses (2,44,88).

Overall, FSTL1 serves diverse regulatory roles in cell proliferation and inflammatory responses through complex MAPK signalling pathways. Findings have revealed that FSTL1 can act as both an activator and an inhibitor of ERK1/2 phosphorylation, depending on the cellular differentiation state and tissue context. In cardiac tissue, FSTL1 activates MAPK pathways (ERK, JNK and p38) through TGF-β1-mediated mechanisms, promoting fibroblast activation and fibrosis. Conversely, during adipocyte differentiation and ciliogenesis, FSTL1 acts as an ERK1/2 antagonist, inhibiting MAPK signalling. These regulatory mechanisms exhibit marked cell- and tissue-specificity, offering potential novel strategies for tumour treatment and inflammatory disease research (33,89). Understanding the regulatory role of FSTL1 in signal transduction may facilitate the development of targeted therapies (17,58,71,90).

The AKT/GSK-3β signalling pathway is crucial for regulating cell survival, proliferation, differentiation and apoptosis (17,91). FSTL1 modulates this pathway through various molecular mechanisms (41,92). At the cellular level, FSTL1 primarily influences signal transduction by modulating AKT protein phosphorylation and activity (Fig. 2), a process involving intricate protein interactions and conformational changes (93,94).

FSTL1 signalling facilitates the conversion of PIP₂ to PIP₃ at the plasma membrane, a critical step indicative of PI3K activation. FSTL1 activates the PI3K/AKT signalling pathway to regulate cell survival and proliferation (41,94). In different disease models, FSTL1 modulates the AKT/GSK-3β pathway in a tissue- and disease-specific manner. In tumour cells, FSTL1 enhances cell proliferation, migration and invasion by promoting AKT pathway activation, whereas in neuroprotective contexts, it exhibits inhibitory and protective effects (91,95).

GSK-3β, a key downstream target of AKT, is also regulated by FSTL1. In neurodegenerative and inflammatory disease models, FSTL1 inhibits GSK-3β activity by regulating its phosphorylation, thereby reducing cellular inflammation and oxidative stress damage (95). This mechanism serves a critical role in neuroprotection and inflammatory regulation, suggesting potential therapeutic applications.

Oxidative stress is a major pathological mechanism in various diseases. FSTL1 exerts potent antioxidant effects through the AKT/GSK-3β signalling pathway. In models of oxidative stress induced by high glucose and inflammation, FSTL1 activates the AKT pathway, inhibiting GSK-3β activity and effectively reducing cellular oxidative damage (96). This mechanism is critical for preventing and treating diabetic complications and neurodegenerative diseases. In multiple disease models, FSTL1 exhibits finely tuned regulatory functions through this pathway, highlighting its essential role in maintaining cellular homeostasis (92,96).

FSTL1 serves a pivotal role in regulating the NLRP3 inflammasome signalling pathway, with its complex molecular mechanisms being critical for the development and progression of inflammatory diseases, such as acute pancreatitis, gout and neuroinflammatory disorders (19,69,97). As a key inflammatory regulatory complex in the innate immune system, the activation of the NLRP3 inflammasome is tightly controlled at multiple levels by FSTL1 (69,98,99).

During the initiation of inflammation, FSTL1 regulates the release of inflammatory mediators by modulating NLRP3 protein conformational changes and aggregation (Fig. 2) (19,69,100). In immune cells, such as macrophages and dendritic cells, FSTL1 inhibits excessive activation of the NLRP3 inflammasome, thereby modulating the intensity and duration of inflammatory responses and helping to maintain immune homeostasis (37,100,101).Oxidative stress is a key trigger for NLRP3 inflammasome activation, and FSTL1 serves an essential regulatory role in this process (101). By regulating the production and clearance of ROS within cells, FSTL1 directly influences the activation threshold of the NLRP3 inflammasome (19,98). In models of oxidative stress induced by high glucose and inflammation, FSTL1 mitigates aberrant NLRP3 inflammasome activation by inhibiting excessive ROS production, thereby reducing inflammatory damage (102,103).

Cellular apoptosis, a critical mechanism in NLRP3 inflammasome regulation, is influenced by FSTL1 through its modulation of caspase-1 activity and apoptotic pathways (97). In models of neurodegenerative and autoimmune diseases, FSTL1 effectively reduces cellular inflammatory damage (17,69,100).

Notably, FSTL1-induced regulation of the NLRP3 inflammasome signalling pathway exhibits notable tissue and disease specificity. Its regulatory mechanisms are complex and variable across different cell types and disease models, offering novel research perspectives for a deeper understanding of the role of FSTL1 in inflammatory regulation (19,37).

FSTL1 has emerged as a multifunctional glycoprotein that orchestrates a wide range of biological processes in both physiological and pathological contexts. Its widespread expression in the heart, lungs, skeletal muscle and joint synovium highlights its critical role in regulating cellular proliferation, differentiation and apoptosis (4-7,17,118). The structural composition of FSTL1, consisting of an N-terminal signal peptide, a follistatin-like domain and a calcium-binding EF-hand domain, enables complex protein-protein interactions that mediate its diverse functions (1-3). Studies have revealed the dual roles of FSTL1 in disease progression, demonstrating both protective and pathogenic effects depending on tissue context, disease stage and microenvironmental factors (17,62,87,118).

In osteoarthritis, the upregulation of FSTL1 in synovial fluid accelerates chondrocyte apoptosis and mitophagy through activation of the TGF-β/Smad2/3 signalling pathways, thus driving disease progression (8,39,44,96). By contrast, in cardiovascular contexts, FSTL1 exhibits cardioprotective properties by promoting angiogenesis following myocardial infarction, acting as a cardiokine that aids cardiac regeneration (2,50,52-55,96).

FSTL1 exerts its diverse biological functions through the intricate regulation of multiple interconnected signalling pathways. The TGF-β/Smad signalling axis is a cornerstone of FSTL1 function, where it serves as both a TGF-β-inducible gene and a modulator of TGF-β receptor complex formation (56-58). Previous mechanistic studies have shown that FSTL1 directly regulates Smad2/3 phosphorylation in a dose-dependent manner, with TGF-β pathway inhibitors effectively reversing FSTL1-induced Smad activation (44,49,148). This bidirectional regulatory network creates a positive feedback loop that amplifies TGF-β-mediated responses in processes ranging from cardiac regeneration to fibrotic pathology.

The NF-κB signalling pathway is regulated in a tissue-specific manner by FSTL1 (27,78), exhibiting context-dependent pro-inflammatory and anti-inflammatory effects. In renal tubular epithelial cells, FSTL1 inhibits NF-κB activation by reducing TNF-α-induced p65 phosphorylation and nuclear translocation, offering protection against kidney fibrosis (67,68). By contrast, in pulmonary and intervertebral disc tissues, FSTL1 positively regulates NF-κB signalling through TLR4/MyD88-dependent pathways, driving inflammatory cytokine production and promoting tissue degeneration (2,68).

The regulation of MAPK signalling by FSTL1 has been refined by recent research, which has demonstrated that FSTL1 functions as an ERK1/2 antagonist during ciliogenesis and preadipocyte differentiation (81), in contrast to its activating role in cardiac fibrosis, where it promotes ERK, JNK and p38 pathway activation via TGF-β1-mediated mechanisms (85-87). This functional plasticity highlights the critical role of cellular differentiation states in determining the signalling outcomes of FSTL1.

The AKT/GSK-3β pathway is another key regulatory node where FSTL1 exerts context-dependent effects on cell survival and stress responses (17,91,149). FSTL1 activates PI3K/AKT signalling, modulating downstream GSK-3β activity through phosphorylation-dependent mechanisms (94). This axis exhibits bidirectional functions: It promotes cell proliferation and invasion in tumour contexts, while providing neuroprotection and antioxidant effects in neurodegenerative and metabolic diseases by inhibiting GSK-3β activity (91,95).

FSTL1 orchestrates innate immune responses by directly regulating the NLRP3 inflammasome (69,98). It modulates NLRP3 protein oligomerisation and controls the release of inflammatory mediators in immune cells. This regulatory mechanism exhibits notable tissue and disease specificity, providing protective effects in inflammatory and autoimmune conditions (100,102,103).

FSTL1 also regulates inflammatory responses through its direct localisation to mitochondria and modulation of MQC. By enhancing electron transport chain activity, FSTL1 promotes NLRP3 inflammasome activation (19,23), while mtROS and released mtDNA trigger inflammatory cascades via the NLRP3 and cGAS-STING pathways (105,106). On the other hand, FSTL1 maintains mitochondrial integrity by regulating mitochondrial dynamics, promoting mitophagy and modulating calcium homeostasis through TMBIM6-VDAC1 interactions, preventing necroptosis (109). This dual regulatory effect highlights the complex roles of the mitochondrial-inflammatory axis.

FSTL1 coordinates vascular and metabolic homeostasis through the integrated regulation of the eNOS and AMPK pathways (16). It activates the AKT-eNOS axis to enhance nitric oxide-mediated angiogenesis and endothelial function in ischemic tissues, while stimulating AMPK signalling to promote glucose uptake, mitochondrial biogenesis and fatty acid oxidation (16). These tissue-specific regulatory mechanisms link exercise-induced myokine secretion to systemic metabolic and cardiovascular benefits.

The therapeutic landscape of FSTL1-targeted interventions includes monoclonal antibody strategies, RNA interference technologies and cell-based therapies. Monoclonal neutralising antibodies are the most clinically advanced approach, demonstrating efficacy in collagen-induced arthritis models by blocking FSTL1-receptor interactions and attenuating downstream signalling. In fibrotic disease models, FSTL1-neutralising antibodies markedly reduce tissue fibrosis by inhibiting fibroblast activation (63,64,122).

siRNA-mediated gene silencing offers precise temporal control of FSTL1 expression, with nanoparticle delivery systems achieving >90% suppression with high target specificity (130). In IVDD models, FSTL1 siRNA-treated MSCs markedly improve disc morphology and function while reducing nucleus pulposus cell apoptosis (2,44). Disease-specific applications have shown promising preclinical results, with recent 2025 investigations expanding the role of FSTL1 as a non-invasive diagnostic biomarker for advanced liver fibrosis (44,60). Plasma FSTL1 levels have demonstrated diagnostic utility in chronic liver diseases (60).

Despite notable progress, the development of FSTL1-targeted therapeutics faces several challenges that must be addressed for successful clinical translation. The tissue-specific and context-dependent nature of FSTL1 regulation presents a fundamental complexity, as identical interventions may produce opposing outcomes depending on the cellular context and disease stage. The concentration-dependent bidirectional regulatory effects of FSTL1 highlight the need for precise dosing and pharmacokinetic control in target tissues. Developing controlled-release formulations, tissue-targeted nanodelivery systems and feedback-regulated expression platforms may help address these pharmacological challenges.

A major translational gap is the lack of validated biomarkers for patient stratification and treatment response monitoring. While plasma FSTL1 levels are associated with disease activity in several conditions, comprehensive biomarker panels that integrate FSTL1 with downstream pathway components are necessary to enable precision medicine approaches (27,60,145).

The absence of large-scale clinical trial data remains the most important barrier to the clinical application of FSTL1-targeted therapeutics. Current evidence largely stems from preclinical models and small-scale human biomarker studies, highlighting the need for rigorously designed clinical trials to establish safety and efficacy. Future research should focus on mechanistic investigations that elucidate tissue-specific regulatory mechanisms and identify context-dependent molecular switches controlling the pro-inflammatory roles of FSTL1 compared with its anti-inflammatory roles. The development of conditional knockout models and inducible expression systems will allow for precise temporal and spatial control, enabling the dissection of stage-specific roles in disease progression.

FSTL1 is a multifaceted molecular regulator at the core of inflammation, fibrosis and tissue remodelling processes. Its intricate regulation of pathways such as TGF-β, NF-κB, MAPK, AKT/GSK-3β and the NLRP3 inflammasome, alongside its novel role in MQC, positions FSTL1 as a master coordinator of cellular homeostasis and stress responses. Therapeutic strategies targeting FSTL1, including monoclonal antibodies, RNA interference and cell-based approaches, have shown promising efficacy in preclinical models of osteoarthritis, rheumatoid arthritis, fibrotic diseases and cardiovascular disorders. The emergence of FSTL1 as both a diagnostic and prognostic biomarker across various disease contexts further highlights its clinical relevance. However, successful clinical translation is dependent on overcoming key challenges, including the complexity of tissue-specific regulation, cardiovascular safety concerns and the development of reliable biomarkers. The integration of multi-omics technologies, precision medicine strategies and advanced drug delivery systems holds the potential to address these obstacles and unlock the therapeutic promise of FSTL1. As mechanistic understanding improves and translational research progresses, FSTL1-targeted therapies are poised to become transformative precision treatments for inflammatory and fibrotic diseases.