Work

Intelligent identification and targeted intervention of GRP75-caused drug resistant hepatocellular carcinoma, a study based on radiomics, machine learning, and molecular pharmacology

Year: 2026

Type: article

Abstract: BACKGROUND: Tumor heterogeneity mediated drug resistance was a core clinical challenge to improve the prognosis of patients with advanced hepatocellular carcinoma (HCC). Glucose-regulated protein 75 (GRP75) was a key molecular target driving this heterogeneity. Therefore, accurate identification of HCC patients with GRP75-related poor prognosis and targeted intervention was a key issue to be solved. MATERIALS AND METHODS: This study integrated radiomics and artificial intelligence (AI) algorithms to construct a preoperative imaging-based risk stratification model, aiming to accurately identify patients with prognosis associated with GRP75. The traditional Chinese medicine (TCM) databases were combined with molecular docking and dynamics simulations techniques to screen for GRP75-targeting TCM monomers. The underlying mechanisms of action were further explored, and functional validation was performed using in vitro and in vivo models. RESULTS: Based on preoperative imaging, we successfully developed a system that could accurately identify HCC patients with poor prognosis associated with high expression of GRP75. Furthermore, the TCM monomer baicalin was identified and validated as a GRP75-targeting agent. Mechanistic studies revealed that baicalin effectively reversed drug resistance in HCC by specifically targeting GRP75 and disrupting the mitochondria-associated endoplasmic reticulum membranes, thereby modulating the calcium/autophagy regulatory axis. This process restored the sensitivity of drug-resistant cells to cisplatin and sorafenib. CONCLUSIONS: This study established an AI-based radiomics system for identifying HCC patients with poor prognosis associated with high expression of GRP75, and revealed a novel therapeutic approach utilizing the TCM monomer baicalin to reverse multi-drug resistance through GRP75 targeting, further clarifying its mechanism.

Source: International Journal of Surgery

DOI: 10.1097/js9.0000000000004913