HSP70: From molecular chaperone to integrative hub in castration-resistant prostate cancer therapeutic resistance.

The emergence of castration-resistant prostate cancer (CRPC), driven by 'undruggable' targets such as androgen receptor splice variant 7 (AR-V7), represents a fundamental barrier to curative therapeutic outcomes. This review proposes a conceptual framework reconceptualizing heat shock protein 70 (HSP70) as a potential integrative hub that may coordinate multiple resistance mechanisms. We synthesize available evidence to explore the hypothesis that HSP70 lies at the nexus of these pathways. We delineate how HSP70 has been reported to be associated with a multidimensional network: stabilizing oncoproteins (AR/AR-V7), potentially contributing to lineage plasticity via Plexin D1 (PLXND1), modulating ferroptosis through the AR-membrane-associated O-acyltransferase domain protein 2 (MBOAT2) axis, and engaging in synthetic vulnerability with heat shock protein 60 (HSP60). Consequently, therapeutic strategies are undergoing a paradigm shift from broad-spectrum inhibition to precision modalities targeting specific HSP70 interactions and functions. We provide a framework for leveraging this hub to overcome CRPC resistance.