LUC7L2 promotes ferroptosis via alternative splicing of SLC7A11 in cisplatin-induced acute kidney injury

Ferroptosis, a key mechanism in acute kidney injury (AKI), is centrally regulated by solute carrier family 7 member 11 (SLC7A11). Studies have shown that the splicing factor LUC7-like 2 (LUC7L2) modulates SLC7A11 in the context of glucose metabolism in cancer cells; however, the potential involvement of this regulatory axis in ferroptosis or renal injury remains unknown. Given the well-established roles of SLC7A11 in ferroptosis, we hypothesize that LUC7L2 may influence renal ferroptosis through SLC7A11 in AKI. Integrated in vitro and in vivo models of cisplatin-induced AKI were established. LUC7L2 expression was modulated by siRNA, plasmid overexpression, and adeno-associated virus 9-mediated knockdown. Ferroptosis was evaluated by cell viability, lipid peroxidation, iron accumulation, glutathione levels, and GPX4 expression. Mechanistic studies included exon-specific splicing assays and RNA immunoprecipitation. Public single-cell RNA sequencing datasets were reanalyzed to define cell–type–specific expression patterns, and the findings were validated in human kidney biopsy specimens and urine samples. The results demonstrate that LUC7L2 expression is upregulated in cisplatin-induced models of AKI. Functionally, it promotes ferroptosis by regulating SLC7A11, thereby reducing glutathione synthesis and exacerbating oxidative stress. We identified a dual-pathway mechanism in which cisplatin-activated p53 represses transcription of SLC7A11 , while LUC7L2 post-transcriptionally controls pre-mRNA splicing of SLC7A11 via direct binding and is associated with increased exon skipping. Under cisplatin stress, LUC7L2 is associated with non-productive SLC7A11 splicing and reduced functional SLC7A11 , thereby promoting ferroptotic susceptibility. In functional assays, we found that renal ferroptotic injury is attenuated by LUC7L2 knockdown but exacerbated by its overexpression. Taken together, these findings identify LUC7L2 as a contributor to cisplatin-induced AKI through splicing-dependent control of SLC7A11 . This study reveals a previously unrecognized post-transcriptional mechanism governing ferroptosis in the kidney and highlights LUC7L2 as a potential diagnostic biomarker and therapeutic target.