Peptidyl-prolyl isomerase PIN1 as a pivotal regulator of cancer progression and therapy

PIN1, a unique phosphorylation-dependent peptidyl-prolyl cis-trans isomerase, serves as a pivotal regulator of oncogenic signaling by catalyzing conformational changes in proteins phosphorylated at Ser/Thr-Pro motifs. Its overexpression across diverse cancers drives tumorigenesis by simultaneously inactivating tumor suppressors and activating oncogenes, thereby promoting uncontrolled proliferation, apoptosis evasion, genomic instability, epithelial-mesenchymal transition (EMT), metastasis, and therapy resistance. PIN1 critically regulates multiple cancer hallmarks via interactions with key pathways, including PI3K/Akt/mTOR, Wnt/β-catenin, NF-κB, and DNA repair machinery. Clinically, PIN1 overexpression correlates with advanced disease stage, poor prognosis, and therapeutic failure, underscoring its value as a prognostic biomarker. Recent breakthroughs in PIN1-targeted therapies demonstrate significant promise. This review aimed to explain PIN1's oncogenic roles and therapeutic targeting in cancer. Direct inhibitors and repurposed agents destabilize oncoproteins, induce "BRCAness" to sensitize tumors to PARP inhibitors, and reverse chemoresistance. Novel strategies, including peptide-based inhibitors and natural compounds, show enhanced selectivity and efficacy in preclinical models. However, challenges persist, including cancer-type heterogeneity in PIN1-driven mechanisms, on-target toxicity risks, and the need for bioavailable inhibitors. Future research must prioritize delineating common core pathways, structure-guided drug design, and biomarker-driven combination therapies. PIN1 inhibition represents a transformative approach to overcome resistance and improve outcomes across malignancies.