Molecular mechanisms, functional diversity, and therapeutic implications of HSP90 isoforms in lung cancer

Heat shock protein 90 (HSP90) is a critical molecular chaperone that ensures the stability and maturation of oncogenic client proteins in lung cancer. This review examines the distinct roles of HSP90α, HSP90β, GRP94 and the mitochondrial paralog TRAP1 in driving disease progression. While HSP90α governs invasiveness and metastasis, HSP90β maintains homeostatic oncogenic signalling. TRAP1 serves as a metabolic lynchpin, facilitating metabolic reprogramming, mitochondrial cytoprotection, and resistance to apoptosis. Together, these isoforms stabilize key drivers such as EGFR, ALK and KRAS, fostering therapeutic resistance. Utilizing systems biology, bioinformatics and comparative analysis of experimental studies, this review explores the high-throughput identification of HSP90 isoforms as central "hub genes" within the lung cancer interactome. The therapeutic potential of mitochondrial-targeted drug delivery systems and isoform-selective inhibitors designed to minimize systemic toxicity are explored in detail. Ultimately, understanding isoform-specific dynamics and multi-omics regulatory networks is essential for developing personalized, selective interventions to overcome drug resistance and improve lung cancer management.