SYVN1-Mediated Degradation of SHMT2 Drives Tubular Injury Progression via Metabolic Reprogramming.

Abstract

Serine hydroxymethyltransferase 2 (SHMT2) is a key mitochondrial enzyme involved in one-carbon metabolism, but its regulation and functional significance in acute kidney injury (AKI) remain unclear. To determine whether SHMT2 downregulation contributes to tubular injury and to elucidate the underlying molecular mechanism, we established murine models of AKI induced by ischemia-reperfusion injury and unilateral ureteral obstruction. In parallel, human proximal tubular HK-2 cells were exposed to hypoxia/reoxygenation or transforming growth factor-β1 stimulation in vitro. We found that SHMT2 expression was markedly reduced in renal tubular epithelial cells across both murine AKI models, showing a significant inverse association with the severity of tubular injury. To elucidate the underlying mechanisms, we subsequently utilized genetic (shRNA) and pharmacological (SHIN1) inhibition of SHMT2, alongside overexpression of the E3 ubiquitin ligase synoviolin (SYVN1). Functional inhibition of SHMT2 aggravated tubular epithelial damage by inducing mitochondrial dysfunction, increasing oxidative stress, promoting the accumulation of nephrotoxic uremic toxins, and impairing both glycolysis and oxidative phosphorylation. Mechanistically, under AKI conditions, elevated SYVN1 directly interacted with SHMT2 via its conserved RING domain, promoting K48-linked polyubiquitination and subsequent proteasomal degradation of SHMT2. Ultimately, this ubiquitin-dependent degradation of SHMT2, mediated by SYVN1, drives AKI progression by inducing metabolic reprogramming and bioenergetic failure in renal tubular cells. These findings highlight the SYVN1/SHMT2 axis as a novel pathogenic mechanism and a promising therapeutic target for preserving tubular metabolic homeostasis and alleviating kidney injury.