Lactate Monocarboxylate Transporter (MCT1/4) Inhibitor Syrosingopine Restores Adaptive Repair in Kidney Injury

Background: Aberrant glycolysis is implicated in maladaptive repair after acute kidney injury (AKI), but therapeutic strategies remain limited. We previously identified MCT4 as a key effector of endothelial hypoxia-induced glycolysis, where its inhibition restored adaptive repair in mice lacking endothelial Prolyl Hydroxylase Domain proteins. Here, we examined whether pharmacologic MCT1/4 inhibition could promote repair in a physiologic context—wild-type mice with intact oxygen sensing subjected to ischemic or obstructive AKI. Methods: Male C57BL/6J wildtype mice underwent renal unilateral ischemia-reperfusion injury (uIRI) or unilateral ureteral obstruction (UUO). Starting at day 2 post-IRI, mice were injected with the MCT1/4 inhibitor syrosingopine (SYR) 7.5 mg/kg or vehicle every other day. Histological, molecular, bulk/sc-RNAseq and metabolomic analyses were performed 7 and 14 days after uIRI. UUO-kidneys were analyzed on day 8 post surgery. Results: Syrosingopine restored kidney damage in IR kidneys as shown by downregulation of mRNAs of profibrotic genes Loxl2, Tgfb1 and proinflammatory Vcam1, Icam1 and reduced collagen deposition relative to vehicle (n=5, P<0.05). Flow cytometry analysis of SYR-treated post-IR kidneys also showed significant reduction in monocyte & macrophage infiltration (n=3-4, P<0.01). Similarly, reduced kidney fibrosis was observed in SYR-treated UUO kidneys relative to vehicle controls (n=6, P<0.05, P<0.01). Bulk RNA seq analysis of SYR-treated day 7 and 14 post-IRI kidneys showed significant downregulation of Interferon gamma response and inflammatory pathways (n=4). Hallmark (GSEA) analysis showed restoration of metabolic health, with upregulation of oxidative phosphorylation and fatty acid metabolism pathways in SYR-treated day 14 IR kidneys relative to vehicle. Metabolomic profiling showed enrichment of TCA, pyruvate and fatty acid metabolic pathways in SYR-treated day 7 post-IR kidneys. Sc-RNA seq analysis showed profound cell-specific metabolic changes in SYR-treated kidneys compared to controls, coupled with significant suppression of macrophage clusters. Conclusion: The MCT1/4 inhibitor syrosingopine reduces AKI to CKD transition by ameliorating fibrosis, inflammation and metabolic dysregulation—highlighting its potential as a novel therapeutic strategy against AKI. Funding: NIDDK Support