Abstract 378: PGRMC1 induced lipid metabolic reprogramming leads to sorafenib resistance in hepatocellular carcinoma.

Abstract Background: Hepatocellular Carcinoma (HCC) is the most predominant type of liver cancer and are often diagnosed at advanced stage resulting in high rates of mortality. Sorafenib is a first-line medication which increases survival by an average of 10.7 months in patients with advanced patients. However, numerous studies have shown that after six months, patients develop resistance to sorafenib treatment. Therefore, understanding the molecular mechanisms of sorafenib resistance (SR) and determining the most promising therapeutic target for the treatment of HCC is of vital importance. Among the various pathways that lead to the development of SR are disruptions in the lipid homeostasis of HCC. PGRMC1, a protein that regulates lipid metabolism and heme stacking, has been recently identified as an onco-target in a number of malignancies. Thus, we have investigated PGRMC1's role in SR in HCC. Methods: We established SR-HCC cell lines (Hep3B, HepG2, and Huh7) through a gradual rise in sorafenib dosage. PGRMC1 expression levels in THLE3 (normal liver cell line), parental HCC, and SR-HCC cell lines was assessed. Genetically modified HCC cell lines with PGRMC1 overexpression or silencing were evaluated for SR using cell viability, apoptosis, colony formation, migration, and invasion assays. To investigate the mechanism of PGRMC1-related SR, we conducted RTPCR using lipoprotein signaling and cholesterol synthesis pathway focused microarray. RT2PCR, immunoblot, and immunofluorescence were utilized to validate the role of PGRMC1 in lipid metabolism associated with SR. Results: PGRMC1 expression was higher in SR-HCC cell lines in comparison to HCC cells and normal liver cells. Furthermore, overexpression of PGRMC1 increased SR, but the silencing of PGRMC1 in HCC and SR-HCC led to the opposite effect. It is interesting to note that our studies revealed that SR-HCC and ovPGRMC1-GFP-Hep3B cells exhibited higher levels of membrane cholesterol and lipid peroxidation in comparison to parental HCC cells. Moreover, our findings indicate that PGRMC1alters lipid metabolism in HCC by upregulating APOC3, HMGCS2, NR0B2, STARD3, and SREBF2, and downregulating APOD. In addition, our data also demonstrates that inhibition of PGRMC1 effectively enhanced the anticancer effect of sorafenib by altering lipid metabolism in HCC. Conclusions: We conclude that PGRMC1 is a feasible target for increasing sorafenib sensitivity through reprogramming lipid metabolism. Citation Format: Poornima Devi Narayanan, Abigail Ramirez, Jazmin Lopez, Mahalakshmi Vijayaraghavan, Alfredo Roman, Kyle Nguyen, Mitchel Amador Rojo, Kariina Garcia, Kritika Soni, Grace Hua, Rajkumar Lakshmanaswamy, Ramadevi Subramani. PGRMC1 induced lipid metabolic reprogramming leads to sorafenib resistance in hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 378.