LRRC8D Suppresses Prostate Cancer Growth and Enhances Platinum Sensitivity via Modulation of CAV-1/STAT3 Signaling.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) that emerges under androgen deprivation and is associated with therapeutic resistance. The contribution of volume-regulated anion channels (VRACs) to this process remains poorly understood. This study identified leucine-rich repeat-containing 8 subunit D (LRRC8D), a VRAC subunit, as the only family member consistently downregulated in NEPC and associated with neuroendocrine (NE)-like features. LRRC8D downregulation was accompanied by suppression of swelling-activated VRAC currents, increased synaptophysin (SYP) expression, decreased cisplatin sensitivity, and neurosecretory remodeling. Conversely, LRRC8D overexpression enhanced cisplatin-induced apoptosis, reduced colony formation, and suppressed tumor growth in xenograft models, including under cisplatin treatment. Consistent alterations in LRRC8D and SYP expression were also observed in enzalutamide-resistant patient-derived organoids. Mechanistically, RE1-silencing transcription factor (REST) promoted LRRC8D transcription. Functional analyses further demonstrated that CAV-1 acted upstream of LRRC8D, and LRRC8D negatively regulated STAT3 activation. Together, these findings indicate that LRRC8D influences PCa phenotype and platinum responsiveness, and implicate a regulatory axis involving LRRC8D and CAV-1/STAT3 signaling in NE-associated features of advanced PCa. Functional analyses further showed that CAV-1 acted upstream of LRRC8D, and LRRC8D negatively regulated STAT3 activation. Together, these findings indicate that LRRC8D influences PCa phenotype and platinum responsiveness and implicate a regulatory axis involving LRRC8D and CAV-1/STAT3 signaling in NE-associated features of advanced PCa.