["The Journal of Physiology, Volume 604, Issue 11, Page 4247-4260, 1 June 2026. ", "\nAbstract figure legend Sodium thiosulfate (STS) rescues the pronephros phenotype of pdx1 morphants through compensatory upregulation of nitric oxide (NO) metabolism. Zebrafish larvae injected with a control morpholino show the typical pronephros structure at 48 h post‐fertilization (hpf) with and without STS treatment. In pdx1 morphants, citrulline concentration is decreased and arginine and proline metabolism show reduced activity, indicating downregulated NO metabolism and leading to pronephros damage at 48 hpf. Treatment with STS resulted in higher arginine and citrulline concentrations, implying an increased production of NO, leading to the rescue of the pronephros of pdx1 morphants at 48 hpf.\n\n\n\n\n\n\n\n\n\nAbstract\nSodium thiosulfate (STS) is gaining increasing attention in research for its potential therapeutic applications across a spectrum of disease processes beyond its current uses. However, the precise mechanisms of action remain incompletely understood. We investigated the efficacy of STS in treating hyperglycaemia‐induced pronephros damage in zebrafish to gain further insight into the underlying mechanisms. Hyperglycaemia was induced in zebrafish by suppressing the pdx1 transcription factor, which plays a crucial role in maintaining physiological pancreatic function. STS was administered by introducing it into the medium of zebrafish larvae. The pronephros structure was analysed at 48 h post‐fertilization. Metabolomic profiling and RNA sequencing were conducted on groups exposed to various experimental conditions. Our findings reveal a downregulation of nitric oxide (NO) signalling in zebrafish with a knocked‐down pdx1 gene, both metabolomically and transcriptionally. Notably, treatment with STS led to a compensatory upregulation of the NO signalling, ultimately resulting in the rescue of the pronephros structure. Our study provides compelling evidence that targeting NO metabolism by the administration of STS offers a promising strategy for addressing hyperglycaemia‐induced organ damage. These findings underscore the potential of STS as a promising therapeutic agent for diabetic complications and warrant further investigation of its clinical applications.\n\n\n\n\n\n\n\n\n\nKey points\n\nSodium thiosulfate (STS) is increasingly drawing attention in research for its potential therapeutic applications across a spectrum of disease processes.\nHere, we demonstrate that STS treatment rescues hyperglycaemia‐induced pronephros damage in zebrafish.\nWe identified upregulation of nitric oxide signalling as the major driver behind STS‐mediated rescue.\nOur data suggest that STS offers a promising strategy for addressing hyperglycaemia‐induced organ damage, including diabetic nephropathy.\n\n\n"]