CYFIP2 deficiency ameliorates renal interstitial fibrosis through attenuating tubular senescence in hypertensive nephropathy

Tubulointerstitial fibrosis is the central pathological feature of hypertensive nephropathy, with cellular senescence being a key driver. Therefore, identifying therapeutic targets in senescent renal tubular epithelial cells is clinically important. The cytoplasmic FMR1-interacting protein (CYFIP) family, which comprises two evolutionarily conserved members, CYFIP1 and CYFIP2, plays crucial roles in neurological regulation. CYFIP2, a key member, is implicated in cytoskeletal dynamics and apoptosis within the nervous system; however, its renal expression pattern and function remain undefined. This study revealed that CYFIP2 expression was significantly upregulated in the renal cortex, particularly in the proximal tubules, of DOCA/salt-induced hypertensive mice, and was positively correlated with the extent of fibrosis. Consistently, CYFIP2 was highly expressed in the renal tubules of patients with hypertensive nephropathy, where its level inversely correlated with the estimated glomerular filtration rate (eGFR). Tubule-specific deletion of CYFIP2 attenuated hypertension-induced cellular senescence (reduced SA-β-gal, p53/p21, and SASP; increased Klotho) and mitigated renal dysfunction, collagen deposition, and epithelial‒mesenchymal transition (EMT). In vitro, CYFIP2 silencing alleviated TGF-β1-induced senescence and fibrosis in HK-2 cells. Mechanistically, CYFIP2 and p53 formed a positive feedback loop that promoted fibrosis by inhibiting the Hippo pathway and enhancing YAP nuclear translocation. The p53 agonist Nutlin-3a reversed the protective effect of CYFIP2 knockout, while the inhibitor Pifithrin-α mimicked this effect. These findings underscore the pivotal role of the CYFIP2/p53-Hippo/YAP axis in hypertensive renal injury, and identify CYFIP2 as a potential therapeutic target. CYFIP2/p53-Hippo signaling drives tubular senescence and renal fibrosis in hypertensive nephropathy.