While mutations in tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase B (SDHB) are well-established drivers of renal cell carcinoma via the accumulation of the oncometabolite succinate, its precise role in renal fibrosis remains entirely unexplored. In this study, we demonstrate that SDHB is down-regulated in fibrotic kidneys. Tubule-specific knockdown of Sdhb exacerbated fibrosis, mitochondrial dysfunction, and inflammation in unilateral ureteral obstruction (UUO) mice, while its overexpression exerted protective effects. Mechanistically, SDHB deficiency induced succinate accumulation, which directly bound to residue Leu150 (L150) of voltage-dependent anion channel 1 (VDAC1), promoting VDAC1 oligomerization and triggering mitochondrial RNA (mtRNA) leakage. Cytosolic mtRNA activated the retinoic acid-inducible gene I (RIG-I)-mitochondrial antiviral signaling protein (MAVS) pathway, driving proinflammatory responses. Pharmacological inhibition of VDAC1 oligomerization by VBIT-4 attenuated mtRNA release. Furthermore, we identified E2F transcription factor 4 (E2F4) as an upstream transcriptional activator of SDHB, and overexpression of E2f4 restored SDHB expression and ameliorated renal pathology. These findings provide mechanistic insights into how TCA cycle disruptions and mtRNA leakage interactions drive renal inflammation, suggesting SDHB as a potential therapeutic target for renal fibrosis.

Cardiovascular-kidney-metabolic (CKM) syndrome is not merely the simple superimposition of isolated target organ lesions, but rather a systemic disorder sustained by a complex network of inter-organ communication. The circadian clock functions as the central spatiotemporal regulator of physiological homeostasis, and the circadian disruption is increasingly recognized as an important contributor to CKM progression. In this review, we systematically elucidate the core mechanisms and biological functions of the circadian clock in mediating inter-organ crosstalk within CKM syndrome. We first delineate the peripheral clock architecture in the heart, kidneys, and crucial metabolic organs, followed by an in-depth analysis of the molecular mediators governing spatiotemporal communication among these organs. Building upon this framework, we further dissect how circadian disruption drives the pathological transition from an early metabolic-inflammatory network imbalance to coupled cardiorenal vascular injury. Finally, we comprehensively summarize multidimensional intervention strategies, encompassing chronopharmacological optimization, lifestyle interventions, and small-molecule modulators targeting the core clock machinery. Ultimately, this review aims to offer a novel chronobiological perspective for decoding inter-organ pathological crosstalk in CKM syndrome, thereby providing a robust scientific rationale for developing circadian-aligned, precision, and multitarget synergistic therapies.

Amelioration of the global diabetes pandemic can be effectively achieved by preventing the development of type 2 diabetes (T2D) among individuals with prediabetes. This approach is particularly important in low and middle-income countries (LMIC), especially India and China, that are home to high and rapidly increasing numbers of individuals with T2D. There is sufficient high-quality evidence, albeit mostly from high-income countries, that T2D can be prevented in those with prediabetes by lifestyle intervention, with or without medication. Similar studies in India and China have shown promising results, with growing evidence also emerging from other LMICs, but wider application of these strategies requires a deeper understanding of the pathophysiology of prediabetes, its heterogeneity and the challenges inherent in their implementation in resource-constrained settings. In particular, there is a pressing need to evaluate effective preventive strategies for individuals with impaired fasting glucose, who constitute a large proportion of those with prediabetes in south Asia and in whom lifestyle intervention appears to be less effective in preventing progression to T2D. Clarity is also needed on the best strategy to prevent diabetes in those individuals who do not have obesity, and on the role of newer drugs (such as the incretin-based therapies) and emerging digital technologies. This article mainly addresses the evidence on diabetes prevention in China and India, where the majority of clinical trials have been conducted.