Ergosterol from edible fungi: Enhancing fatty acid oxidation <i>via</i> CPT1A to protect against diabetic kidney disease

<i>Background</i>: Diabetic kidney disease (DKD), a common microvascular complication of diabetes mellitus, is recognized as a leading cause of end-stage renal disease. Ergosterol, a natural sterol abundant in edible fungi, has shown pharmacological effects that may benefit DKD treatment. However, its precise mechanisms of action remain elusive. This study aimed to evaluate the therapeutic efficacy of ergosterol in DKD and to delineate the underlying mechanisms. <i>Methods</i>: Transcriptome microarray sequencing data from DKD patients retrieved from the public GEO database, as well as data from mouse DKD models, were analyzed to identify differentially expressed genes. Db/db mouse, high-glucose-induced HK-2 cells and conditioned THP-1 cells were employed to evaluate the impact of ergosterol on renal function, lipid metabolism, and macrophage phenotypic transformation. <i>Results</i>: Transcriptional profiling of DKD kidneys revealed alterations in fatty acid metabolism, which were corroborated in db/db mice. Ergosterol significantly improved renal function, reduced lipid accumulation, and mitigated inflammation. CPT1A, a key modulator of fatty acid metabolism, was identified as a target. The inhibition of CPT1A in renal tubular epithelial cells led to impaired fatty acid oxidation and lipid accumulation. Excessive renal lipids further stimulated macrophages to transform into pro-inflammatory phenotypes, leading to renal inflammation infiltration and exacerbating kidney damage. Ergosterol upregulated CPT1A expression through transcriptional regulation of FOXA1, thereby reducing lipid accumulation and subsequent renal inflammation. <i>Conclusion</i>: Ergosterol enhances renal fatty acid oxidation <i>via</i> the FOXA1/CPT1A pathway, reducing renal lipid accumulation and inflammation, potentially delaying DKD progression. This study elucidates the therapeutic potential of ergosterol in DKD therapy and provides new insights into the treatment of this disease.