Trim21 mediates metabolic reprogramming in renal tubular cells via PFKP ubiquitination to alleviate renal fibrosis

Chronic kidney disease (CKD), stemming from varied nephric impairments, manifests a steadily escalating global incidence. As a progressive pathological condition, CKD is typified by an intensification in the gravity of renal interstitium fibrotic transformations. Nonetheless, the intrinsic mechanisms underpinning nephric fibrosis remain elusive. In this context, we elucidated a marked augmentation in aerobic glycolysis within proximal tubular epithelial cells (TECs) of CKD patients, alongside unilateral ureteral obstruction (UUO) and ischemia‐reperfusion injury (IRI) murine models, concomitant with deficiency of Trim21. Experimental investigations, both in vivo and in vitro, revealed that Trim21 deficiency aggravates the aberrantly heightened aerobic glycolysis, thereby exacerbating fibrotic reaction progression. Concomitantly, enhancive glycolytic flux paralleled an elevation in ATP genesis and reconstitution of cytoskeletal architecture. Mechanistically, we uncovered that Trim21 modulates aerobic glycolysis in TECs via ubiquitin‐facilitated degradation of phosphofructokinase platelet (PFKP), thus attenuating nephric fibrosis. Collectively, our insights posit Trim21 as a prospective therapeutic target in the amelioration of renal fibrosis. In brief, after UUO or IRI injury, the structure and function of TECs are impaired. TECs with failed repair revealed significantly increased glucose consumption, enhanced glycolytic flux and added lactate production. More importantly, Trim21 mediates the ubiquitination and degradation of PFKP, a key glycolytic enzyme. The dysfunction and structural changes of TECs induces the inhibition of Trim21, and the degradation of PFKP is hindered, resulting in increased abundance, which further aggravated the aerobic glycolysis of TECs.