Targeting SRSF6 to Enhance Cisplatin Sensitivity by Modulating Redox Balance via NFE2L1 exon 4 Splicing in ESCC

The mechanisms by which cancer cells survive and adapt under high levels of reactive oxygen species (ROS) remain poorly understood, especially in the context of redox homeostasis. This study reveals increased oxidative stress in esophageal squamous cell carcinoma (ESCC), with serine/arginine-rich splicing factor 6 (SRSF6) playing a crucial role in maintaining redox homeostasis. SRSF6 binds to the exonic splicing enhancer (ESE) motif in nuclear factor erythroid 2-related factor 1 (NFE2L1) Exon 4, preventing exon skipping and promoting the production of specific isoforms that promote ESCC cell proliferation. This interaction enhances cellular antioxidant capacity, thereby influencing redox balance. Moreover, reducing SRSF6 increases the levels of NFE2L1-S, the isoform produced by exon 4 skipping in the NFE2L1 gene, which elevates ROS levels and induces apoptosis and ferroptosis. Notably, SRSF6 and NFE2L1 form a positive feedback loop: NFE2L1 serves as the transcription factor for SRSF6, while SRSF6 acts as the splicing factor for NFE2L1. Antisense oligonucleotides (ASOs) targeting SRSF6 significantly suppress ESCC cell growth. Importantly, inhibiting this feedback loop also enhances cisplatin (CDDP) sensitivity, increasing the therapeutic efficacy of CDDP. Our findings highlight the critical role of the SRSF6-NFE2L1 axis in redox homeostasis and tumor progression, positioning SRSF6 as a distinctive therapeutic target to improve treatment outcomes in ESCC.