Chloride intracellular channel CLIC3 mediates fibroblast cellular senescence by interacting with ERK7.

Cellular senescence (CS) is recognized as a critical driver of aging and age-related disorders. Recent studies have emphasized the roles of ion channels as key mediators of CS. Nonetheless, the roles and regulatory mechanisms of chloride intracellular channels (CLICs) during CS remain largely unexplored. In this study, we conducted RNA sequencing on bleomycin-induced senescent lung tissues from mice and identified Clic3 as the most significantly upregulated CLIC member. Furthermore, our findings revealed that the knockdown of CLIC3 mitigated intracellular chloride ion lose, mitochondrial dysfunction, nuclear enlargement, DNA damage, CS progression, and expression of senescence-associated secretory phenotype (SASP) triggered by bleomycin. Mechanistically, CLIC3 controls CS by translocating to the membrane where it interacts with extracellular signal-regulated kinase 7 (ERK7). Overall, our work demonstrates that the chloride intracellular channel CLIC3 modulates CS by repressing ERK7 activity and provides novel insights into the role of chloride channels.