Therapeutic Synergy of Silibinin‐Loaded Nanogel and Low‐Dose Gamma Radiation in Hepatocellular Carcinoma: Emphasis on EMT, Angiogenesis, and Immune Response

ABSTRACT The mechanisms driving hepatocellular carcinoma (HCC) progression are governed by a complex interplay among epithelial‐mesenchymal transition (EMT), inflammation, angiogenesis, and impaired immune response. This study explored the efficacy of a pH‐sensitive silibinin‐loaded nanogel (NSB) combined with low‐dose radiation (LDR) in modulating these mechanisms. Male Wistar rats (180–220 g) are divided into seven groups (n = 6): control, LDR (0.25 Gy/week), NSB (25 mg/kg), HCC, HCC+LDR, HCC+NSB, and HCC+LDR+NSB. Combined treatment with LDR and NSB significantly upregulated CDH1 expression while decreasing the transcription levels of TWIST1 , ROCK1 , TNF‐α , RELA , HIF1A , CXCL12 , CXCR4 , VEGF , and CD274 , compared to the untreated HCC group and the corresponding monotherapy groups (P < 0.05). Additionally, immunological analyses revealed a notable decline in serum interleukin (IL)‐6 levels and a concurrent increase in IL‐12, accompanied by enhanced CD8 expression relative to the untreated HCC group and monotherapy groups (P < 0.05). Moreover, LDR+NSB regimen effectively enhanced hepatic function indices, mitigated oxidative damage driven by diethylnitrosamine (DEN), and augmented endogenous antioxidant activities, compared to the untreated HCC and single‐treatment groups (P < 0.05). In conclusion, these results suggest that the synergistic integration of NSB with LDR represents a promising multi‐targeted approach for attenuating key drivers of HCC progression while augmenting adaptive anti‐tumor immune responses.