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.