FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic...

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.