Combining ferroptosis inducers with gemcitabine to enhance treatment efficacy in pancreatic cancer.

Abstract

BACKGROUND: Gemcitabine (GEM) is a standard chemotherapy for pancreatic cancer, but resistance limits its clinical benefit. The role of SRRM1, a splicing regulator, in GEM resistance remains unclear. METHODS: The expression and prognostic significance of SRRM1 were analyzed in clinical datasets and validated by Western blotting and immunohistochemistry. GEM-resistant pancreatic cancer cell lines were established, and functional assays including colony formation, apoptosis, and CFDA staining were conducted to assess SRRM1's role in chemoresistance. RNA-seq and KEGG enrichment analyses were performed to explore downstream pathways. Ferroptosis was evaluated by C11-BODIPY staining, iron/MDA/GSH quantification, and mitochondrial function assays. NRF2's regulatory effect on SRRM1 was assessed using gain- and loss-of-function experiments. A pancreatic cancer xenograft model was used to validate the therapeutic relevance in vivo. RESULTS: SRRM1 was significantly upregulated in pancreatic cancer and associated with poor prognosis and GEM resistance. Knockdown of SRRM1 suppressed tumor growth, enhanced GEM sensitivity, and induced ferroptosis, as evidenced by increased lipid peroxidation and mitochondrial damage. Rescue experiments confirmed the ferroptosis-suppressive function of SRRM1. Notably, we identified NRF2 as an upstream transcriptional activator of SRRM1, forming a pro-survival NRF2-SRRM1 axis that suppresses ferroptosis and promotes GEM resistance. Combining GEM with the ferroptosis inducer RSL3 yielded synergistic antitumor effects in vivo, especially in SRRM1-high tumors. CONCLUSION: This study suggests that SRRM1 may serve as a predictive biomarker for GEM response in pancreatic cancer. Targeting SRRM1 in conjunction with ferroptosis inducers could offer a promising strategy to overcome GEM resistance.

Key Findings

• SRRM1 is upregulated in pancreatic cancer and correlates with poor prognosis and gemcitabine resistance.
• Knockdown of SRRM1 enhances gemcitabine sensitivity and induces ferroptosis by increasing lipid peroxidation and mitochondrial damage.
• NRF2 acts as an upstream transcriptional activator of SRRM1, forming a NRF2-SRRM1 axis that suppresses ferroptosis and promotes chemoresistance.
• Combining gemcitabine with the ferroptosis inducer RSL3 produces synergistic antitumor effects, particularly in tumors with high SRRM1 expression.

Clinical Significance

Citation

Zhang Hanyun, Lu Wenjie. Combining ferroptosis inducers with gemcitabine to enhance treatment efficacy in pancreatic cancer. Cancer & metabolism. 2026-Apr-11.