Glycolysis-Driven Renal Fibrosis in Chronic Kidney Disease: Emerging Mechanisms and Therapeutic Opportunities
INTRODUCTION Chronic kidney disease (CKD) is a growing global health burden, with increasing prevalence and mortality rates closely associated with population aging.[1] Affecting over 10 percent of the worldwide population, including nearly half of adults aged 70 and older, CKD has become both a major public health challenge and an urgent global healthcare priority.[2] Pathologically, a key feature of CKD is tubulointerstitial fibrosis, which characterizes the chronic and progressive course of the disease, eventually leading to irreversible renal functional impairment. Although fibrogenic signaling cascades, particularly the transforming growth factor-β (TGF-β)/Smad and Wnt/β-catenin pathways,[2] have been well characterized in the molecular pathogenesis of CKD, emerging evidence suggests that dysregulated renal aerobic glycolysis may be a novel metabolic driver of fibrosis.[3,4] However, the precise mechanistic links between these pathways and fibrotic progression are incompletely understood, and no clinically viable therapies currently target these processes. Recent studies have revealed that cellular aerobic glycolysis plays an important role not only in acute kidney injury (AKI) but also in the transition from AKI to CKD and CKD progression.[2,3] Apart from its primary role in energy production, aerobic glycolysis and its metabolic derivatives have been shown to regulate multiple pathophysiological processes, including extracellular matrix synthesis, cellular proliferation, autophagy, and apoptosis.[5] Notably, Han et al., in Redox Biology, demonstrated that renal tubular epithelial cells undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis in both CKD patients and murine models. This shift is mediated by sclerostin (Sost) and interferon-stimulated gene 20 (Isg20) signaling.[5] The consequences of this metabolic reprogramming are profound: Enhanced aerobic glycolysis sustains renal epithelial cell viability while promoting excessive extracellular matrix deposition, the hallmark of fibrotic kidney disease. Although Sost gene deletion has been reported to promote renal interstitial fibrosis with little mechanistic clarity,[6] Han et al. observed consistent downregulation of Sost expression in renal tubules from both CKD patients and murine models (unilateral ureteral obstruction [UUO] and folic acid [FA]-induced CKD). Remarkably, genetic restoration of Sost expression inhibited aerobic glycolysis, thereby attenuating tubular injury and fibrosis and supporting its protective role. Subsequently, the authors employed the TurboID proximity labeling technique in conjunction with co-immunoprecipitation (Co-IP) and identified evidence of a direct molecular interaction between Sost and Isg20. Parallel investigations revealed Isg20 to be a glycolysis-associated factor whose expression increased with CKD progression and was positively correlated with histological fibrosis severity. Mechanistically, Sost acts as an endogenous inhibitor of Isg20-driven aerobic glycolytic flux, thereby mitigating fibrotic progression. The discovery of the Sost-Isg20 regulatory axis reveals a previously unrecognized pathway in renal fibrogenesis with significant therapeutic implications. Current therapeutic options for renal fibrosis remain limited, as no clinically approved antifibrotic agents exist. Natural products, however, continue to provide a valuable source of pharmacologically active compounds, as demonstrated by extensive pharmacognosy research.[7,8] This study highlights the natural compound hederagenin (HDG) as a particularly promising candidate.[7] While HDG exhibits diverse pharmacological activities, including antitumor and anti-inflammatory effects, prior work by the same team demonstrated its inhibition of the janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in adriamycin-induced nephropathy.[9] The present study reveals a distinct renoprotective mechanism: dual modulation of the Sost-Isg20 axis through upregulation of Sost expression and suppression of Isg20-mediated glycolytic flux. Nevertheless, systemic elevation of Sost raises potential cardiovascular safety concerns, necessitating further investigation.[10] Future research should prioritize kidney-specific delivery systems to minimize off-target effects, detailed mechanistic studies of Sost-Isg20 signaling, and comprehensive safety evaluations of hederagenin derivatives. Such efforts will facilitate the translation of findings targeting this metabolic pathway into safe and novel therapeutic strategies for CKD. In conclusion, this study identified the Sost-Isg20-aerobic glycolysis axis as a novel therapeutic target in renal fibrosis. Hederagenin demonstrates antifibrotic efficacy by upregulating Sost and inhibiting Isg20. Future studies should further investigate the therapeutic potential of targeting renal glycolysis in CKD and its role in the bidirectional transition between AKI and CKD. Integrating insights from natural compounds will also be essential for identifying novel metabolic interventions.
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