Inhibition of eCIRP attenuates PANoptosis and renal fibrosis

Extracellular cold-inducible RNA-binding protein (eCIRP) was discovered as a potent damage-associated molecular pattern (DAMP). It has been shown that eCIRP is linked to various types of programmed cell death and acute inflammation. However, the role of eCIRP in chronic inflammation and renal fibrosis has not been elucidated. Accumulating evidence indicates that renal tubular epithelial cells (RTECs) play a significant role in renal fibrosis. C23, a small molecular peptide inhibitor of eCIRP, has been implicated as a therapeutic agent in the context of acute inflammation and tissue injury. PANoptosis or synchronized cell death is observed as simultaneous triggering of apoptosis, pyroptosis, and necroptosis. However, its role in renal fibrosis is not known. We therefore hypothesize that eCIRP induced-chronic inflammation and injury in RTECs are mediated by PANoptosis and that inhibition of eCIRP by C23 decreases RTEC PANoptosis and attenuates renal injury and fibrosis in a mouse model of unilateral ureter obstruction (UUO) injury. By using primary RTECs, we demonstrated that eCIRP induces inflammatory cytokines, Z-DNA-binding protein-1, and other PANoptosome markers and markers of apoptosis, pyroptosis, and necroptosis. We then substantiated that C23 downregulated proinflammatory cytokines and inhibited PANoptosis in the RTECs. Using the UUO mouse model, we demonstrated renal cell PANoptosis and renal fibrosis 7 days after UUO. Importantly, treatment with C23 effectively inhibited PANoptosis and concurrently ameliorated renal fibrosis. Taken together, eCIRP induces inflammation and PANoptosis in RTECs, whereas C23 inhibits PANoptosis in these cells and attenuates renal fibrosis in UUO mice.<b>NEW & NOTEWORTHY</b> Renal fibrosis is a common pathological manifestation of chronic kidney disease (CKD). Extracellular cold-inducible RNA-binding protein (eCIRP) was discovered as a potent damage-associated molecular pattern (DAMP). eCIRP is linked to various types of programmed cell death. PANoptosis or synchronized cell death is observed as simultaneous triggering of apoptosis, pyroptosis, and necroptosis. Inhibiting eCIRP by C23, a small molecular peptide inhibitor of eCIRP, attenuated PANoptosis and renal fibrosis in CKD.