Abstract
BACKGROUND: Prostate cancer (PCa) is a globally prevalent malignancy in males and is imposing an increasing epidemiological burden. The androgen receptor (AR) signalling axis is fundamentally implicated in PCa tumorigenesis and disease progression. Although androgen deprivation therapy (ADT) elicits transient therapeutic responses in the majority of cases, progression to castration-resistant prostate cancer (CRPC) remains an almost universal clinical trajectory. Dysregulated lipid homeostasis, manifesting as intracellular lipid deposition, has been mechanistically linked to CRPC pathogenesis and therapeutic failure under enzalutamide regimens. However, effective strategies to mitigate lipid accumulation in PCa remain elusive. METHODS: STARD4, a key gene involved in lipid metabolism, was identified as functionally significant in PCa through integrated bioinformatics analysis of public databases. RT‒qPCR, western blot analysis, and IHC staining were performed to evaluate STARD4 expression, while Kaplan-Meier survival analysis, Gleason score, and tumor stage were performed to assess its clinical significance in PCa. The biological functions of STARD4 and its contribution to enzalutamide resistance were elucidated through in vitro and in vivo experiments. The effect of STARD4 on abnormal lipid accumulation in PCa cells was evaluated by Oil Red O (ORO) staining, while its impact on endoplasmic reticulum (ER) stress was assessed through ER-tracking imaging and transmission electron microscopy (TEM). Mechanistic exploration involves a combination of techniques, including RNA-seq analysis, Gene ontology analysis, coimmunoprecipitation (Co-IP), and GST pull-down assay, to analyse the interactions and potential mechanisms involving STARD4, AR, and E3 ubiquitin ligase UBE4B. RESULTS: In this study, we observed that STARD4 expression was markedly reduced in PCa tissues and was correlated with an adverse prognosis. STARD4 overexpression inhibited PCa cell proliferation, migration, and lipid accumulation while promoting apoptosis through ER stress. Mechanistically, STARD4 enhanced the interaction between UBE4B and AR, facilitating AR ubiquitination and degradation and thus suppressing AR signalling. Additionally, the upregulation of STARD4 expression enhanced sensitivity to enzalutamide in resistant cells by diminishing lipid accumulation and inhibiting the AR signalling pathway. In summary, STARD4 functions as a tumour suppressor in PCa by regulating cholesterol metabolism and modulating AR signalling. CONCLUSIONS: Our findings identify STARD4 as a promising therapeutic target for reversing enzalutamide resistance in PCa while also providing novel insights for future research on lipid metabolism within the tumour microenvironment.