MMP7-Triggered mitophagy by regulating parkin-mediated ubiquitination of VDAC1 confers anoikis resistance in the epithelium of hyperplastic prostate.

Benign prostatic hyperplasia (BPH), prevalently in aging men, is characterized by aberrant cell death of prostate cells. Anoikis, a specific subtype of apoptosis, is triggered when cells detach from the extracellular matrix (ECM), in contrast, cells with anoikis resistance contribute to pathological processes such as unregulated cell proliferation and impaired cell death. However, the role of anoikis resistance in BPH pathogenesis remains poorly understood. In this study, an elevated anoikis resistance level was observed in BPH tissues compared to normal prostates. Furthermore, matrix metalloproteinase 7 (MMP7) was identified as a key regulator of anoikis resistance in hyperplastic prostatic epithelium. Under anoikis-inducing conditions, MMP7 promoted mitophagy via the PINK1-Parkin pathway, alleviated mitochondrial stress damage, and enhanced anoikis resistance in BPH-1 cells. Mechanistically, MMP7 interacted with VDAC1 and bound specifically to lysine residues K109 and K110, thereby inhibiting VDAC1 oligomerization and increasing the accumulation of VDAC1 monomers, which served as additional binding sites to Parkin-mediated polyubiquitination. Moreover, clinical data revealed that MMP7 expression levels correlated significantly with the International Prostate Symptom Score (IPSS) and nocturia frequency. Additionally, in vivo experiments demonstrated that inhibition of MMP7 suppressed mitophagy and markedly attenuated prostatic epithelial hyperplasia in a rat model BPH. Collectively, our findings clarify the functional role of the MMP7-VDAC1 axis in BPH pathogenesis and highlight its potential as a therapeutic target for BPH management.