Phellinus linteus polysaccharides inhibit castration-resistant prostate cancer progression possibly via dual modulation of PIK3R1 and PGC-1α: a preclinical evaluation.

Castration-resistant prostate cancer (CRPC) remains a major challenge due to limited treatment options and frequent therapeutic resistance. This study demonstrates that Phellinus linteus polysaccharides (PLP), both in the form of drug-loaded serum and as a purified extract, exhibit potent anti-CRPC activity through a dual-axis molecular mechanism. In a castrated PC-3 xenograft model, PLP (400 mg/kg/day) suppressed tumor volume growth by 91.7% and tumor weight growth by 78.0% compared with the control group, showing efficacy comparable to abiraterone/prednisone without hepatorenal toxicity. In vitro, both 30% PLP-containing serum and purified PLP inhibited proliferation, migration, and invasion, and promoted apoptosis while reducing intracellular reactive oxygen species levels in PC-3 and 22RV1 cells. Integrative transcriptomic and multi-omics analyses revealed coordinated downregulation of phosphatidylinositol 3-kinase-protein kinase B-mechanistic target of rapamycin signaling and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Functional validation showed that overexpression of phosphoinositide-3-kinase regulatory subunit 1 rescued PLP-induced tumor suppression, whereas knockdown of PGC-1α abolished its antioxidative and antiproliferative effects, indicating that both pathways are critically involved. These findings suggest that PLP combats CRPC by simultaneously inhibiting oncogenic signaling and mitigating oxidative stress, positioning it as a promising natural therapeutic candidate for CRPC.