Galectin‐1 regulates scar hyperplasia by modulating NASP variable splicing to generate ROS

Abstract Galectin‐1, a constituent of the mammalian β‐galactoside‐binding lectin family, plays a pivotal regulatory role in fibrotic cascades. Dysregulated fibrogenic cellular activity has been implicated as a critical driver of hypertrophic scar (HS) pathogenesis. Nevertheless, the precise mechanistic contributions and molecular pathways through which Galectin‐1 modulates HS development remain incompletely characterized. qRT‐PCR and western blot techniques were employed to explore the expression of Galectin‐1 in hypertrophic scar tissues and cells. The Galectin‐1 knockdown cell line was established by utilizing the lentivirus approach, and the influences of Galectin‐1 on cellular biological functions were examined. The molecular mechanism underlying Galectin‐1 regulation was investigated via RNA‐seq analysis, immunofluorescence, and Western blot. Subsequently, RNA‐seq combined with RT‐PCR was used to investigate Galectin‐1's role in HS alternative splicing. Galectin‐1 exhibits significant overexpression in pathological HS tissues and activated fibroblasts. Genetic silencing of Galectin‐1 effectively attenuates hypertrophic scar fibroblast (HSF) cell proliferation, migration, and invasive capacities while downregulating fibrotic molecular markers. Transcriptomic and functional analyses reveal that Galectin‐1 orchestrates concurrent PANoptosis and ferroptosis in fibrogenic cells. Galectin‐1 regulates PANoptosis through the ROS pathway by modulating the ES alternative splicing of NASP, and this process depends on HNRNPL. Overall, Galectin‐1 influences the PANoptosis process in HSF cells by modulating the alternative splicing of NASP, thereby regulating the fibrotic cascade. Our findings indicate that Galectin‐1 is a critical regulator of HS formation, offering a novel therapeutic target and direction for HS treatment.