What question did this study set out to answer?

This study aims to elucidate the mechanisms by which solamargine induces apoptosis and ferroptosis in intrahepatic cholangiocarcinoma.

April 26, 2026Scientific Reports0 citationsOpen Access

Solamargine induces apoptosis and ferroptosis through the ROS/p38 MAPK signalling pathway in intrahepatic cholangiocarcinoma

XWXiang WangDalian Medical University KLKai LuoFujian Medical University HBHe BaiDalian Medical University

Key Points

This study aims to elucidate the mechanisms by which solamargine induces apoptosis and ferroptosis in intrahepatic cholangiocarcinoma.
In vitro and in vivo experiments using ICC cell lines (HUCCT-1 and HCCC-9810) and normal biliary epithelial cells (HIBEC).
Used transcriptome sequencing and gene set enrichment analysis (GSEA) to explore signaling pathways.
Conducted western blot analysis and pharmacological inhibition assays to investigate p38 MAPK activation.
Solamargine significantly inhibited ICC cell proliferation, migration, and invasion while sparing normal biliary epithelial cells (HIBEC).
In vivo studies showed that solamargine reduced tumor growth in both orthotopic and subcutaneous ICC mouse models with enhanced tolerability compared to gemcitabine.
Increased markers of apoptosis and ferroptosis, along with robust activation of p38 MAPK in tumor tissues, were observed.

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver malignancy with rising global incidence and poor prognosis. Despite recent advances in treatment strategies, effective therapeutic options for ICC remain limited. Solamargine (SM), a natural steroidal alkaloid, has demonstrated anticancer activity, yet its mechanisms in ICC are not fully understood. This study shows that SM inhibits ICC progression by inducing both apoptosis and ferroptosis in vitro and in vivo. SM significantly suppressed proliferation, migration, and invasion of ICC cells (HUCCT-1 and HCCC-9810), with minimal cytotoxicity toward normal biliary epithelial cells (HIBEC). Mechanistically, SM induced mitochondrial dysfunction, ROS accumulation, and lipid peroxidation, leading to apoptosis and ferroptosis. Transcriptome sequencing and gene set enrichment analysis (GSEA) revealed that SM treatment activated apoptosis- and ferroptosis-related pathways, including MAPK signaling. Western blot analysis and pharmacological inhibition assays confirmed that p38 MAPK activation was essential for SM-induced cell death, with ROS acting as an upstream activator. In vivo, SM significantly inhibited tumor growth in both orthotopic and subcutaneous ICC mouse models and showed better tolerability than gemcitabine. Tumor tissue analysis further confirmed increased markers of apoptosis and ferroptosis, along with p38 MAPK activation. These findings suggest that SM exerts dual antitumor effects in ICC, which are associated with the induction of apoptosis and ferroptosis and may involve the ROS/p38 MAPK signaling axis, highlighting its potential as a therapeutic candidate for ICC.

Ask AI

Helpful

Bookmark

View Full Paper