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FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review)

  • Authors:
    • Zhi Li
    • Xiaolei Liu
    • Hesong Zeng
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 30
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    Published online on: November 24, 2025
       https://doi.org/10.3892/ijmm.2025.5701
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Abstract

Protein homeostasis, or proteostasis, refers to the integrated quality control systems that regulate protein synthesis, folding, post‑translational modification, trafficking and degradation to maintain proteome stability and function. Disruption of these processes, including abnormal synthesis, misfolding or impaired degradation, results in proteostasis collapse and underlies the pathogenesis of cancer, neurodegeneration, cardiovascular disease and metabolic syndromes. Recent studies have highlighted FK506‑binding proteins (FKBPs), a family of immunophilins defined by a conserved peptidyl‑prolyl cis‑trans isomerase domain, as pivotal modulators of proteostasis. By modulating protein folding, stabilizing complexes, regulating endoplasmic reticulum stress and directing selective degradation, FKBPs establish direct links between proteostasis regulation and disease progression. This review presents the first comprehensive synthesis of FKBP‑mediated control of proteostasis across diverse clinical contexts. It analyzed how their structural features confer regulatory potential and elucidate their roles in proteome remodeling in cancer, pathogenic protein aggregation in neurodegenerative disorders, ion channel stabilization in cardiovascular dysfunction and kinase phosphorylation in metabolic regulation. By integrating these diverse actions within a unified proteostasis framework, FKBPs are proposed as versatile regulators and promising therapeutic targets, providing new perspectives on the proteostasis‑disease axis and opportunities for precision intervention across multiple organ systems.
View Figures

Figure 1

Overview of proteostasis and its core
pathways. Proteostasis is maintained through a dynamic balance of
protein synthesis, folding and post-translational modifications,
and degradation. (A) Protein synthesis. Ribosomes translate mRNA
into nascent polypeptide chains, which often require assistance
from molecular chaperones and foldases to achieve stable
structures. (B) Protein folding and post-translational
modifications. Newly synthesized proteins fold in the ER and
undergo PTMs, such as phosphorylation, sumoylation, acetylation and
lactylation, which regulate protein stability, activity and
interactions. (C) Protein degradation. Misfolded, damaged or
surplus proteins are eliminated through two major pathways: The
UPS, where substrates are sequentially ubiquitinated by E1, E2 and
E3 enzymes and degraded by the 26S proteasome into peptides; and
the ALP, where cytoplasmic substrates, including protein aggregates
and damaged organelles, are sequestered into autophagosomes, fused
with lysosomes and degraded into reusable biomolecules. Together,
these pathways establish a quality control cycle that preserves
proteome integrity and cellular homeostasis under both
physiological and stress conditions. P, phosphorylation; sumo,
sumoylation; Ac, acetylation; Lactyl, lactylation; UPS,
ubiquitin-proteasome system; ALP, autophagy-lysosome pathway; E1,
ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3,
ubiquitin ligase; ER, endoplasmic reticulum; AMP, adenosine
monophosphate; PPi, inorganic pyrophosphate; PTMs,
post-translational modifications; Ub, ubiquitin.

Figure 2

Structural diversity and subcellular
localization of FKBP family members. Schematic representation of
FKBPs, organized by their predominant localization in the
cytoplasm/nucleus or ER/mitochondria. The figure illustrates the
modular architecture of FKBPs and highlights how distinct domains
support their functional diversity in protein homeostasis. All
family members share the conserved PPIase domain, which catalyzes
proline isomerization to accelerate protein folding and
conformational stabilization. Several larger members, such as
FKBP51 and FKBP52, also contain TPR domains that mediate docking to
heat shock protein 90, enabling scaffold functions in protein
folding, complex stabilization and nuclear receptor trafficking.
Members including FKBP13, FKBP19, FKBP22, FKBP23, FKBP60 and FKBP65
harbor N-terminal ER signal peptides and ER retention motifs, which
target them to the ER lumen for the folding and assembly of
secretory and membrane proteins. FKBP38 contains a C-terminal
transmembrane anchor that localizes it to mitochondria and
facilitates anti-apoptotic Bcl-2 recruitment, linking FKBPs to
apoptosis and mitophagy regulation. Additional modules such as
EF-hand motifs and Ca2+-binding domains provide
responsiveness to calcium signaling, further expanding functional
versatility. Together, this structural heterogeneity enables FKBPs
to regulate protein folding, modification, trafficking and
degradation across diverse subcellular compartments. PPIase,
peptidyl-prolyl cis-trans isomerase; TPR, tetratricopeptide repeat;
ER, endoplasmic reticulum; EF-hand, helix-loop-helix
calcium-binding motif; FKBPs, FK506-binding proteins.

Figure 3

ER-resident and cytoplasmic FKBPs
regulate proteostasis to support tumor progression. Schematic
illustration of how representative FKBPs contribute to protein
homeostasis in cancer. In the ER, FKBP9 binds to BiP to maintain
folding equilibrium and suppress excessive IRE1α-XBP1 activation,
protecting cells from ER stress-induced apoptosis. FKBP7 interacts
with BiP in cancer-associated fibroblasts to modulate collagen
subtype secretion, favoring extracellular matrix remodeling and
tumor invasion. FKBP10 regulates substrate maturation and
localization, including retention of prelamin A in the ER and
stabilization of type I procollagen through cooperation with Hsp47,
and also supports translational efficiency at the ribosome. Outside
the ER, FKBP51 functions as a scaffold that shapes
post-translational modifications and autophagic turnover: It
recruits PHLPP to regulate AKT dephosphorylation, promotes Akt
ubiquitination via TRAF6 and directs TIMP3 degradation through the
Beclin1 complex, thereby modulating survival signaling and
microenvironment remodeling. FKBP52 acts as an Hsp90 co-chaperone
that stabilizes steroid hormone receptors such as AR and ERα,
facilitates their nuclear transport via dynein and enhances
transcriptional activation of oncogenic programs. Collectively,
these mechanisms highlight how distinct FKBPs integrate ER stress
responses, protein folding, post-translational regulation and
receptor signaling to maintain proteostasis and promote malignant
progression. FKBP, FK506-binding protein; ER, endoplasmic
reticulum; BiP, binding immunoglobulin protein (GRP78); IRE1α,
inositol-requiring enzyme 1α; XBP1s, X-box binding protein 1
spliced isoform; UPR, unfolded protein response; CAF,
cancer-associated fibroblast; PPIase, peptidyl-prolyl cis-trans
isomerase; AKT, protein kinase B; PHLPP, PH domain and leucine-rich
repeat protein phosphatase; TRAF6, TNF receptor-associated factor
6; TIMP3, tissue inhibitor of metalloproteinases 3; AR, androgen
receptor; ERα, estrogen receptor α; Hsp, heat shock protein; IKKα,
IκB kinase α; DHT, dihydrotestosterone; Ub, ubiquitin; BRCA1,
breast cancer 1, early onset.

Figure 4

FKBPs regulate neuronal protein
homeostasis through distinct mechanisms in neurodegenerative
diseases. (A) FKBP12 accelerates α-synuclein misfolding and
aggregation via prolyl isomerization, promoting Parkinson's disease
pathology. Pharmacological inhibition of FKBP12 by rapamycin or the
non-immunosuppressive compound ElteN378 suppresses α-SYN
aggregation, conferring neuroprotective effects. (B) FKBP51
modulates tau proteostasis through the Hsp90 chaperone complex,
balancing tau aggregation and stabilization in Alzheimer's disease.
The Hsp90-FKBP51-tau complex promotes pathogenic tau
oligomerization, while the p23-FKBP51-tau complex stabilizes tau in
a non-aggregated state, exerting a protective effect. (C) Under
physiological conditions, FKBP52 facilitates tau degradation
through the autophagy-lysosome pathway. However, its abnormal
elevation enhances tau hyperphosphorylation and aggregation,
contributing to neurofibrillary tangle formation and
neurodegeneration. α-SYN, α-synuclein; PD, Parkinson's disease; AD,
Alzheimer's disease; FKBP, FK506-binding protein; Hsp, heat shock
protein.

Figure 5

FKBP12.6 stabilizes RyR2 conformation
to prevent pathological Ca2+ leak in heart failure and
atrial fibrillation. Under physiological conditions (left),
catecholamine stimulation activates PKA and CaMKII, but RyR2
channels on the SR remain stabilized in the closed state by
FKBP12.6, preventing diastolic Ca2+ leak and preserving
Ca2+ cycling. In pathological settings such as heart
failure and atrial fibrillation (right), sustained sympathetic
drive and oxidative stress induce PKA hyperphosphorylation at
Ser2809, CaMKII phosphorylation at Ser2814 and oxidative
modifications of RyR2. These alterations disrupt FKBP12.6 binding,
destabilize the channel complex and promote aberrant
Ca2+ leak. The resulting cytosolic Ca2+
overload contributes to delayed afterdepolarizations,
arrhythmogenic activity and progressive cardiac dysfunction.
FKBP12.6, FK506-binding protein 12.6; RyR2, ryanodine receptor 2;
SR, sarcoplasmic reticulum; PKA, protein kinase A; CaMKII,
calcium/calmodulin-dependent protein kinase II; ROS, reactive
oxygen species; P, phosphorylation; GAS, GMP-AMP synthase; NCX,
sodium-calcium exchanger; AC, adenylyl cyclase.

Figure 6

FKBP51 regulates metabolic
homeostasis by scaffolding kinase phosphorylation across multiple
tissues. Schematic representation of FKBP51-mediated regulation of
metabolic signaling. (A) In the MBH, FKBP51 interacts with WIPI4 to
recruit LKB1 to the AMPK complex, enhancing AMPK phosphorylation
and ULK1 activation to promote autophagy, while binding WIPI3-TSC2
to inhibit mTORC1 signaling. (B) In pancreatic β cells, FKBP51
scaffolds the phosphatase PHLPP to AKT, facilitating
dephosphorylation of AKT at Ser473 and decreasing FOXO1
phosphorylation, which preserves FOXO1 transcriptional activity and
supports β-cell differentiation, maturity and stress adaptation.
(C) In adipose tissue, FKBP51 suppresses AKT activity, indirectly
modulating p38 MAPK-mediated phosphorylation of PPARγ and GR,
thereby balancing lipogenesis and lipolysis. Together, these
mechanisms highlight FKBP51 as a dose-sensitive scaffold that
fine-tunes kinase phosphorylation to coordinate glucose
utilization, lipid storage and energy sensing, ultimately
maintaining systemic metabolic homeostasis. AMPK, AMP-activated
protein kinase; mTORC1, mechanistic target of rapamycin complex 1;
ULK1, UNC-51-like kinase 1; LKB1, liver kinase B1; WIPI, WD repeat
domain phosphoinositide-interacting protein; PHLPP, PH domain
leucine-rich repeat protein phosphatase; AKT, protein kinase B;
FOXO1, forkhead box protein O1; GR, glucocorticoid receptor; PPARγ,
peroxisome proliferator-activated receptor γ; MAPK,
mitogen-activated protein kinase; MBH, mediobasal hypothalamus;
HSP90, heat shock protein 90.
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Copy and paste a formatted citation
Spandidos Publications style
Li Z, Liu X and Zeng H: FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review). Int J Mol Med 57: 30, 2026.
APA
Li, Z., Liu, X., & Zeng, H. (2026). FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review). International Journal of Molecular Medicine, 57, 30. https://doi.org/10.3892/ijmm.2025.5701
MLA
Li, Z., Liu, X., Zeng, H."FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57.1 (2026): 30.
Chicago
Li, Z., Liu, X., Zeng, H."FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 30. https://doi.org/10.3892/ijmm.2025.5701
Copy and paste a formatted citation
x
Spandidos Publications style
Li Z, Liu X and Zeng H: FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review). Int J Mol Med 57: 30, 2026.
APA
Li, Z., Liu, X., & Zeng, H. (2026). FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review). International Journal of Molecular Medicine, 57, 30. https://doi.org/10.3892/ijmm.2025.5701
MLA
Li, Z., Liu, X., Zeng, H."FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57.1 (2026): 30.
Chicago
Li, Z., Liu, X., Zeng, H."FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 30. https://doi.org/10.3892/ijmm.2025.5701
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