Intelligent identification and targeted intervention of GRP75-caused drug resistant hepatocellular carcinoma, a study
Zhendong Wang1,2, Jianguo Zhu3, Ziyi Wang1,2
1School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, China.
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.
Insights
Harnessing artificial intelligence and radiomics, this study identifies hepatocellular carcinoma (HCC) patients with poor prognosis linked to GRP75. The traditional Chinese medicine compound baicalin effectively targets GRP75 to overcome drug resistance.
Area of Science:
- Oncology
- Radiology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) presents a significant clinical challenge due to tumor heterogeneity and drug resistance.
- Glucose-regulated protein 75 (GRP75) is identified as a key driver of this heterogeneity and poor prognosis in HCC.
- Accurate identification and targeted intervention for GRP75-related HCC are crucial for improving patient outcomes.
Purpose of the Study:
- To develop a preoperative imaging-based risk stratification model for identifying HCC patients with GRP75-associated poor prognosis.
- To screen for traditional Chinese medicine (TCM) monomers targeting GRP75.
- To elucidate the mechanism by which TCM monomers reverse drug resistance in HCC.
Main Methods:
- Integration of radiomics and artificial intelligence (AI) algorithms for risk model construction.
- Utilizing TCM databases, molecular docking, and dynamics simulations to identify GRP75-targeting TCM monomers.
- In vitro and in vivo functional validation of identified agents and their mechanisms.
Main Results:
- An AI-based radiomics system accurately identified HCC patients with poor prognosis linked to high GRP75 expression.
- The TCM monomer baicalin was identified and validated as a GRP75-targeting agent.
- Baicalin reversed multi-drug resistance in HCC by targeting GRP75, disrupting mitochondria-associated endoplasmic reticulum membranes, and modulating the calcium/autophagy axis, restoring sensitivity to chemotherapy.
Conclusions:
- An AI-powered radiomics system can effectively identify HCC patients with GRP75-driven poor prognosis.
- The TCM monomer baicalin represents a novel therapeutic strategy for overcoming multi-drug resistance in HCC via GRP75 targeting.
- The study clarifies the mechanism of baicalin's action, offering a new avenue for HCC treatment.
