The ER is the principal site for protein synthesis, folding and quality control, and its homeostasis is indispensable for sustaining the rapid growth and survival of cancer cells. Disruption of ER proteostasis caused by high translational demand and oncogenic stress activates adaptive mechanisms such as the UPR, which enables tumor cells to tolerate proteotoxic stress and resist apoptosis. Several FKBPs localize to the ER lumen. Among them, FKBP7, FKBP9 and FKBP10 (hereafter referring to the protein) have been most extensively studied in the context of tumor biology.

FKBP9 and FKBP7 help tumor cells adapt to increased protein synthesis and folding pressure by regulating the ER proteostasis network. FKBP9 forms a complex with the molecular chaperone BiP to support correct protein folding and assembly, maintaining folding equilibrium within the ER. In glioblastoma, FKBP9 inhibits the IRE1α-XBP1 signaling pathway and suppresses CHOP-mediated apoptosis, preventing overactivation of the UPR and enhancing resistance to ER stress (39). FKBP9 expression correlates positively with BiP levels, and their co-expression is associated with poor prognosis, underscoring its key role in ER homeostasis (40).

FKBP7 contributes to proteostasis and extends its influence to the tumor microenvironment. In pancreatic ductal adenocarcinoma, FKBP7 is highly expressed in cancer-associated fibroblasts (CAFs). By competing with BiP, FKBP7 alters the secretion of collagen subtypes, reducing type I and increasing type IV collagen. This promotes a dense extracellular matrix that restricts immune infiltration and supports tumor invasion (41). These functions demonstrate that FKBP7 modulates both ER stress adaptation and extracellular matrix remodeling (Fig. 3).

Unlike FKBP9 and FKBP7, FKBP10 plays a distinct role in protein homeostasis that is less dependent on classical ER stress signaling. FKBP10 primarily contributes to proteostasis by regulating substrate folding and subcellular localization. Through its PPIase domain, FKBP10 binds directly to specific client proteins to influence their conformational maturation and intracellular trafficking. In bladder cancer, FKBP10 binds prelamin A, leading to its retention in the ER and preventing its translocation into the nucleus, thereby disrupting Lamin A formation and nuclear structure (42). This results in nuclear atypia and enhances the migratory and invasive capacity of cancer cells. In glioma, FKBP10 interacts with Hsp47 via its third PPIase domain to promote the folding and stabilization of type I procollagen, which directly facilitates extracellular matrix organization and the establishment of a tumor-supportive microenvironment (10).

Beyond its role in folding and localization, FKBP10 also supports translational homeostasis in highly proliferative cancer cells. Its conserved PPIase domain catalyzes the isomerization of proline residues in nascent polypeptides, accelerating translation elongation, particularly for proline-rich ribosomal and structural proteins. Loss of FKBP10 impairs this isomerization process, leading to ribosomal stalling at proline motifs and reduced synthesis of proline-rich proteins, underscoring the dependence of such proteins on FKBP10-mediated PPIase activity. In non-small cell lung cancer (NSCLC), FKBP10 localizes to the ribosomal catalytic center, reinforcing its function in supporting translation (43). Loss of FKBP10 or impairment of its enzymatic activity reduces translation efficiency, impairs cell cycle progression and induces apoptosis. FKBP10 is upregulated in multiple malignancies, including NSCLC, colorectal cancer, renal cell carcinoma, bladder cancer and glioma, and is associated with poor prognosis (44-46). Its knockdown not only inhibits proliferation and migration but also sensitizes tumor cells to chemotherapy and targeted therapies, highlighting its potential as a therapeutic target (Fig. 3).

In conclusion, FKBP7, FKBP9 and FKBP10 are ER-resident FKBPs that regulate proteostasis through distinct mechanisms. FKBP9 and FKBP7 primarily participate in unfolded protein responses and protein folding control, while FKBP10 governs translational efficiency and substrate localization. These proteins enable cancer cells to manage translational stress and maintain proteome integrity under oncogenic pressure, linking ER proteostasis to malignant progression. Targeting the functional domains of these FKBPs may offer promising therapeutic strategies for cancers characterized by dysregulated protein homeostasis and elevated ER stress.

PTMs are key regulatory mechanisms that control protein function, stability and subcellular localization. They play a critical role in maintaining cellular homeostasis and in coordinating responses to external stimuli. In the tumor microenvironment, PTMs are extensively involved in signal transduction, cell cycle regulation, metabolic reprogramming and immune evasion (47). Dysregulation of PTMs is closely linked to tumor initiation, progression and treatment resistance.

FKBP51 (also known as FKBP5) has emerged as a critical regulator that integrates PTM-dependent signaling with protein stability and cellular adaptation. FKBP51 contributes to tumor progression by modulating phosphorylation, ubiquitination and acetylation of key signaling proteins, thereby shaping the functional output of oncogenic pathways.

One of the core functions of FKBP51 is to modulate PTMs of key signaling proteins, maintaining the integrity of signaling complexes and regulating downstream signaling outputs. A well-characterized example is its bidirectional regulation of the Akt pathway. In melanoma, FKBP51 interacts with Hsp90 to enhance K63-linked ubiquitination of Akt, which increases Akt stability and activity, thereby activating downstream effectors such as P70S6K and Cyclin D1 to promote cell proliferation (48). By contrast, in prostate and pancreatic cancers, FKBP51 enhances its interaction with PH domain and leucine-rich repeat protein phosphatase (PHLPP), facilitating dephosphorylation of Akt at Ser473 and attenuating Akt activity, thereby suppressing survival signaling (49). The direction of FKBP51-mediated Akt regulation depends on factors such as PHLPP expression, Hsp90 status and FKBP51's own PTM state, reflecting its functional plasticity as a scaffold protein within signaling complexes (Fig. 3).

Furthermore, in castration-resistant prostate cancer, FKBP51 forms a complex with PHLPP and inhibitor of NF-κB kinase subunit α to inhibit both Akt and NF-κB pathways (50). In melanoma, FKBP51 enhances acetylation of the transcription factor YY1, which suppresses the expression of the pro-apoptotic death receptor 5 and reduces sensitivity to apoptosis triggered by TNF-related apoptosis-inducing ligand (51). These findings collectively indicate that FKBP51 modulates key signaling pathways by coordinating phosphorylation, ubiquitination and acetylation, thereby enabling tumor cells to adapt and survive in hostile microenvironments.

In addition, FKBP51 regulates protein stability and degradation by mediating selective autophagic turnover of specific substrates. In clear cell renal cell carcinoma, FKBP51 binds to the metalloproteinase inhibitor tissue inhibitor of metalloproteinases 3 (TIMP3) and recruits it to the Beclin1 autophagy complex, promoting its lysosome-dependent degradation. Since TIMP3 inhibits extracellular matrix degradation, its downregulation facilitates tumor cell invasion (52). This suggests that FKBP51 contributes to tumor microenvironment remodeling by modulating the stability and degradation of specific proteins (Fig. 3).

In summary, FKBP51 maintains protein homeostasis by coordinating PTMs and selective degradation. Through its roles in signal regulation, apoptosis resistance and microenvironment adaptation, FKBP51 supports sustained proliferation, migration and therapy resistance in tumor cells, highlighting its potential as a key regulator of proteostasis and a promising therapeutic target.

FKBP52 (also known as FKBP4) is a key co-chaperone within the Hsp90 complex. In various cancers, its oncogenic role is closely linked to the regulation of nuclear receptor stability, activity and subcellular localization. A central mechanism involves its ability to assemble and stabilize hormone receptor-chaperone complexes, enhance receptor conformational integrity and facilitate their nuclear translocation. Through its TPR domain, FKBP52 binds to Hsp90 and forms a stable chaperone complex (53). Its PPIase domain further modulates the conformation of steroid receptors-such as androgen receptor (AR), estrogen receptor α (ERα) and glucocorticoid receptor (GR)-via prolyl isomerization, thereby enhancing ligand binding and transcriptional activity (54,55). In breast and prostate cancers, FKBP52 increases the abundance and activity of ERα and AR, and its elevated expression is strongly associated with tumor progression and poor prognosis (56,57).

Notably, FKBP52 plays a critical role in regulating the subcellular trafficking of nuclear receptors. Upon ligand binding, FKBP52 facilitates the recruitment of the dynein motor complex to the receptor-Hsp90 complex. This interaction promotes active transport of the receptor complex along microtubules toward the nucleus, enabling efficient nuclear import through the nuclear pore complex. This nuclear translocation is essential for receptor-mediated transcriptional activation. For instance, FKBP52 enhances GR nuclear accumulation and transcriptional output by supporting its interaction with the dynein complex (58). Similarly, FKBP52 promotes the nuclear import of RelA (p65) in the NF-κB pathway by stabilizing its association with Hsp70, thereby amplifying NF-κB transcriptional activity and contributing to tumor proliferation and inflammatory signaling (59) (Fig. 3).

In summary, FKBP52 acts as a molecular scaffold that regulates both the stability and nuclear localization of key transcriptional regulators. By coordinating the chaperoning, transport and activation of nuclear receptors and signaling proteins, FKBP52 helps maintain protein homeostasis and promotes cancer cell growth and adaptation. These findings highlight FKBP52 as a critical node in oncogenic signaling and a promising therapeutic target.

PD is a prevalent neurodegenerative disorder primarily characterized by the selective degeneration of dopaminergic neurons in the substantia nigra, leading to impaired motor function (62,63). Although the precise mechanisms underlying the disease remain incompletely elucidated, accumulating evidence indicates that the aberrant aggregation of α-Syn constitutes a critical pathological hallmark of PD (64). α-Syn is a widely expressed cytoplasmic protein that normally participates in the regulation of synaptic function. However, in PD, α-Syn undergoes pathological aggregation into fibrillar structures within neurons, forming Lewy bodies, which in turn induce neurotoxicity and contribute to neurodegeneration (65).

Investigations have revealed that the PPIase activity of FKBPs and their role in modulating protein folding are intricately linked to the aggregation of α-Syn (66). FKBP12 contributes to the pathogenesis of PD through multiple mechanisms that disrupt proteostasis. It directly interferes with the folding and aggregation of α-Syn by binding to its proline-rich C-terminal region and catalyzing cis/trans isomerization of terminal prolines, inducing pathogenic conformational changes in the monomer. This markedly accelerates and alters aggregation kinetics, promoting the formation of highly branched dendritic structures (66). In addition, FKBP12 forms a complex with calcineurin under conditions of sustained cytosolic Ca²⁺ elevation induced by α-Syn toxicity. This complex drives pathological dephosphorylation of key presynaptic proteins involved in vesicle trafficking, endocytosis and cytoskeletal organization, including growth associated protein 43 and brain acid soluble protein 1. The resulting synaptic dysfunction destabilizes dopamine transporters at the plasma membrane, reduces dopamine release and leads to neuronal death (67). Given FKBP12's pivotal role in the disease process, targeting this protein represents a promising strategy for disease-modifying therapeutic interventions. A recent study demonstrated that rapamycin, through the inhibition of FKBP12 independent of the mTORC1 pathway, confers neuroprotective effects, underscoring FKBP12 as a novel therapeutic target for PD (68). Furthermore, non-immunosuppressive FKBP12 inhibitors, such as ElteN378, have shown efficacy in preventing α-Syn aggregation, presenting a potential new class of therapeutics for early-stage PD treatment (69) (Fig. 4A). However, challenges remain in achieving adequate brain penetration and isoform selectivity for these compounds, which may limit their translational applicability and require further optimization.

In summary, FKBP12, through its PPIase activity, disrupts neuronal proteostasis via multiple pathways, including the regulation of α-Syn conformation, alteration of its aggregation dynamics and calcineurin-dependent dephosphorylation of synaptic proteins. These processes collectively drive the onset and progression of PD. The multifaceted role of FKBP12 in disease pathogenesis not only reveals a new dimension of proteostasis imbalance in PD but also provides a solid theoretical foundation and potential avenues for the development of disease-modifying therapies targeting FKBP12.

AD is a progressive neurodegenerative disorder characterized by cognitive decline, with hallmark pathological features including β-amyloid plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau protein (70-72). Tau, a microtubule-associated protein, undergoes conformational alterations and aggregation that are considered central to the neuronal dysfunction and cell death observed in AD (71,73-75). In recent years, FKBP51 and FKBP52 have garnered increasing attention for their regulatory roles in tau pathology.

FKBP51 promotes tau oligomer formation through cooperation with Hsp90. Hsp90 functions as a scaffold, precisely positioning the proline-rich region of tau into the PPIase catalytic pocket of FKBP51, thereby catalyzing proline cis/trans isomerization. This process alters tau conformation and phosphorylation status, accelerating oligomer accumulation. The resulting changes enhance tau pathogenicity, disrupt neuronal proteostasis and drive the progression of neurodegeneration (76). By contrast, FKBP51 can also form a complex with the Hsp90 co-chaperone p23, whose negatively charged C-terminal tail binds to the positively charged, aggregation-prone repeat domain of tau, inhibiting its fibrillization kinetics. When p23 and FKBP51 are both present, a p23-FKBP51-tau ternary complex may form, partially counteracting the aggregation-promoting effect of FKBP51 and exerting a protective regulatory influence on tau aggregation (77). These findings indicate that FKBP51 can either exacerbate or suppress tau aggregation depending on its interaction partners, with the functional outcome determined by the composition and dynamic balance of the chaperone network (Fig. 4B).

In parallel, FKBP52 plays a pivotal role in regulating tau protein homeostasis, influencing both its degradation and the formation of pathological aggregates (78). Under tau proteotoxic stress, FKBP52 localizes to perinuclear lysosomal clusters and supports the function of the ALP, promoting lysosomal degradation of tau and preventing its abnormal secretion, thereby limiting extracellular tau propagation (12). By contrast, abnormally elevated FKBP52 levels markedly enhance tau hyperphosphorylation and aggregation, with a more pronounced pathological effect in the aged brain. This pro-aggregation activity is not only associated with its regulation of tau conformation and aggregation kinetics through the Hsp90 chaperone network, but may also involve activation of glial cells and the release of inflammatory mediators, creating a feedforward loop between tau aggregation and neuroinflammation that accelerates neuronal injury (79). These findings indicate that FKBP52 exerts dual, context-dependent effects on tau pathology, with its regulatory direction shifting under different physiological and pathological conditions, providing important insights into the progression of tauopathies and potential therapeutic strategies (Fig. 4C).

Collectively, FKBP51 and FKBP52 play multifaceted and context-dependent roles in tau proteostasis. They act through distinct yet overlapping mechanisms, including PPIase activity, Hsp90 co-chaperone interactions and regulation of the autophagy-lysosome pathway. Depending on the cellular context, they can either promote or restrain tau aggregation. This dual regulation shifts the balance between neuronal resilience and degeneration, highlighting their importance as modulators of AD progression and as potential therapeutic targets. An important unresolved question is what specific cellular or pathological cues dictate whether FKBP51 and FKBP52 act to promote or suppress tau aggregation, a topic that warrants further investigation.

In cardiomyocytes, RyR2 is the primary calcium release channel on the sarcoplasmic reticulum (SR), and its protein homeostasis is essential for regulating cardiac contractility and rhythm (82,83). During excitation-contraction coupling, RyR2 channels open in response to membrane depolarization, releasing stored Ca²⁺ from the SR into the cytosol to initiate contraction. In diastole, RyR2 channels are expected to remain closed to prevent abnormal Ca²⁺ efflux and allow for Ca²⁺ reuptake and myocardial relaxation (84,85). However, in HF and arrhythmias such as atrial fibrillation (AF), dysregulation of the RyR2 macromolecular complex leads to pathological diastolic Ca²⁺ leak, disrupting cytosolic Ca²⁺ homeostasis (86,87). This Ca²⁺ dysregulation promotes delayed afterdepolarizations and triggered activity, forming a shared pathological basis for HF and AF (88).

Within the RyR2 complex, FKBP12.6, also known as calstabin2, acts as a key stabilizer of channel structure and function. Cryo-electron microscopy studies reveal that RyR2 assembles as a homotetramer, with one FKBP12.6 molecule binding to each protomer at specific interfacial regions. These sites are located between the helical domain and SPRY domains, where FKBP12.6 stabilizes the closed conformation of the channel (89). Its binding extends the mean closed time of RyR2, suppresses spontaneous openings and promotes coupled gating between adjacent channels, thereby preventing Ca²⁺ leakage in the resting state (90).

Under pathological conditions, particularly during sustained sympathetic activation or oxidative stress, RyR2 homeostasis becomes disrupted. Post-translational modifications such as protein kinase A-mediated hyperphosphorylation at Ser2808, cysteine oxidation and S-nitrosylation result in the dissociation of FKBP12.6 from the channel complex (15). This destabilizes the closed conformation of RyR2, increases the open probability and promotes diastolic Ca²⁺ leak, which in turn contributes to Ca²⁺ overload, electrophysiological instability and progressive cardiac dysfunction (91,92).

Multiple animal models support the central role of FKBP12.6 in RyR2 regulation. In murine models of HF, RyR2 channels exhibit increased Ser2808 phosphorylation and oxidative modifications, accompanied by reduced FKBP12.6 binding. These alterations correlate with enhanced Ca²⁺ leak and reduced contractility (93). Mice lacking FKBP12.6 develop spontaneous arrhythmias, whereas FKBP12.6 overexpression or treatment with rycals such as S107 restores FKBP12.6 binding to RyR2, stabilizes channel closure, reduces aberrant Ca²⁺ release and improves cardiac function. Importantly, rycals do not directly block RyR2 openings but enhance FKBP12.6 affinity for the channel, thereby stabilizing the RyR2 macromolecular complex at a structural level (94). Similar mechanisms are observed in AF, where atrial myocytes from patients with AF and animal models show increased RyR2 phosphorylation and oxidation, decreased FKBP12.6 binding and elevated diastolic Ca²⁺ spark frequency. FKBP12.6-deficient mice, despite having structurally normal hearts, exhibit enhanced susceptibility to pacing-induced AF. Treatment with S107 suppresses this phenotype only in the presence of FKBP12.6, indicating its essential role in the therapeutic effect (94) (Fig. 5).

In summary, maintenance of RyR2 protein homeostasis is critical for normal cardiac function. FKBP12.6 plays a pivotal role in stabilizing the RyR2 complex and preventing pathological Ca²⁺ leak. Therapeutic strategies targeting the FKBP12.6-RyR2 interaction, particularly with rycal compounds, offer a promising approach for precision treatment of HF and arrhythmias.

In the central nervous system, FKBP51 influences metabolic balance by modulating the activity of key kinases in the autophagy pathway. Autophagy initiation requires activation of AMP-activated protein kinase (AMPK) and is inhibited by mechanistic target of rapamycin complex 1 (mTORC1) (97). AMPK activation depends on phosphorylation of its upstream kinase liver kinase B1 (LKB1) at Thr172, whereas mTORC1 activity is suppressed by the tuberous sclerosis complex (TSC)1/2 complex (98). Members of the WD repeat domain phosphoinositide-interacting (WIPI) protein family, WIPI4 and WIPI3, act as scaffolds for LKB1-AMPK and TSC2, respectively, coupling energy sensing to autophagy regulation (99,100). FKBP51 interacts with WIPI4 to recruit LKB1 to the AMPK complex, enhancing Thr172 phosphorylation and promoting UNC-51-like kinase 1 (ULK1) phosphorylation at Ser555 to initiate autophagy. In parallel, FKBP51 binds the WIPI3-TSC2 complex to cooperatively inhibit mTORC1 activity, further relieving autophagy suppression (16).

The physiological relevance of these scaffold-based mechanisms is supported by in vivo findings demonstrating their dose-dependent effects on energy homeostasis and autophagy regulation. In vivo, this regulation shows a clear dose dependency. Mediobasal hypothalamus-specific deletion of FKBP51 reduces AMPK-ULK1 activation, enhances mTORC1 signaling, decreases autophagy and leads to obesity, impaired glucose tolerance and increased food intake. Moderate FKBP51 overexpression enhances AMPK activity and autophagy in skeletal muscle and adipose tissue, inhibits mTORC1 signaling, improves insulin sensitivity and limits weight gain under high-fat diet conditions (101). By contrast, excessive FKBP51 expression activates AKT-mTORC1 signaling, suppresses autophagy and disrupts proteostasis. This bidirectional effect of deficiency and overexpression highlights FKBP51 as a dose-sensitive regulator of autophagy and metabolic balance (102) (Fig. 6A). In glucose metabolism, FKBP51 modulates the AKT-forkhead box protein O1 (FOXO1) signaling axis in pancreatic β cells to regulate cell function and survival. AKT is a serine/threonine kinase activated by phosphorylation at Thr308 and Ser473 downstream of insulin receptor-PI3K-pyruvate dehydrogenase kinase 1/mTORC2 signaling (103). Activated AKT phosphorylates the transcription factor FOXO1 at Ser256, promoting its nuclear export and repressing the transcription of target genes (104,105). FOXO1 is essential for β-cell differentiation, maturity and stress adaptation (106,107). As a scaffold protein, FKBP51 recruits the phosphatase PHLPP to AKT, facilitating dephosphorylation at Ser473 and reducing AKT activity. This decreases FOXO1 Ser256 phosphorylation, promotes its nuclear retention and preserves transcriptional activity. Under inflammatory stress, this mechanism helps maintain β-cell function, enhance survival and sustain glucose-stimulated insulin secretion, forming a protective FKBP51-PHLPP-AKT-FOXO1 regulatory pathway (16,108) (Fig. 6B).

In lipid metabolism, FKBP51 influences two key nuclear receptors in adipocytes, peroxisome proliferator-activated receptor γ (PPARγ) and glucocorticoid receptor (GR), to balance lipogenesis and lipolysis. The p38 mitogen-activated protein kinase phosphorylates PPARγ at Ser112, decreasing its transcriptional activity and suppressing lipogenesis, while phosphorylation of GR enhances its transcriptional activity, promoting lipolysis (109). FKBP51 suppresses AKT activity, which indirectly reduces p38 activation, thereby lowering GR phosphorylation and lipolytic gene transcription while relieving inhibitory phosphorylation of PPARγ to enhance lipogenic activity (16). FKBP51, as part of the Hsp90 chaperone complex, also retains GR and PPARγ in the cytoplasm, preventing their nuclear translocation and phosphorylation (31). Upon ligand binding, FKBP52 replaces FKBP51 in the GR complex, enabling GR nuclear import, whereas PPARγ is released from FKBP51 by protein phosphatase 5 to dephosphorylate Ser112 and restore activity (16). Notably, during early adipocyte differentiation, FKBP51 translocates from mitochondria to the nucleus, where it binds GRα and inhibits its transcriptional activity, linking stress signaling to lipid metabolic gene expression in a time-dependent manner (110) (Fig. 6C).

Collectively, these findings establish FKBP51 as a central scaffold that orchestrates kinase phosphorylation to fine-tune metabolic signaling. By bridging phosphatases and kinases such as AKT, p38, AMPK and mTORC1, FKBP51 exerts precise control over glucose utilization, lipid storage and autophagy. This scaffold-dependent regulation allows cells to dynamically adapt to nutritional and stress cues, thereby safeguarding systemic metabolic balance. Importantly, the dose-sensitive nature of FKBP51 underscores its dual capacity to either maintain homeostasis or drive metabolic dysfunction, highlighting its significance as a pivotal regulator of proteostasis within energy metabolism.