Lipid metabolic disorder aggravates calcium oxalate-induced crystal deposition and kidney injury through inhibiting the AMPK–Echs1 pathway

The global incidence of kidney stone disease, particularly calcium oxalate (CaOx) stones, is rising, paralleling the epidemic of metabolic syndrome. Although lipid metabolism disorders are recognized risk factors, the precise molecular mechanisms linking impaired fatty acid metabolism to kidney stone pathogenesis remain poorly defined. Our study uncovers a novel metabolism–immune axis underlying this crystal nephropathy. We established a mouse model of metabolic dysfunction-associated crystal nephropathy by combining long-term high-fat diet (HFD) with glyoxylate (GLY) injections. Multi-omics analyses profiled renal metabolic alterations. Furthermore, we used mice with kidney tubular cell-specific Echs1 overexpression and pharmacological AMP-activated protein kinase (AMPK) activation by 5-aminoimidazole-4-carboxamide ribonucleotide, with supporting studies in HK-2 cells exposed to palmitate and oxalate. Importantly, clinical evidence from patient kidney tissues and blood samples supports the translational relevance of these preclinical findings, suggesting that the key molecular alterations are also observed in human disease. HFD exacerbated CaOx crystal-induced renal injury and deposition. Multi-omics revealed profound dysregulation of fatty acid metabolism and mitochondrial dysfunction. Crucially, HFD/GLY suppressed the expression of Enoyl-CoA hydratase, short-chain 1 (Echs1), a key mitochondrial β-oxidation enzyme, in a manner dependent on reduced AMPK phosphorylation. This suppression drove mitochondrial impairment (including dysfunction and cristae disruption) and renal tubular cell apoptosis, and promoted​ pro-inflammatory M1 macrophage polarization. Strikingly, kidney-specific overexpression of Echs1 or pharmacological activation of AMPK alleviated HFD/GLY-induced renal injury, mitochondrial defects, and crystal deposition. These findings were corroborated in cellular models and supported by evidence of downregulated Echs1 in human stone-forming kidneys. Overall, we demonstrate that disruption of the AMPK–Echs1 axis in kidney leads to defective fatty acid oxidation and mitochondrial dysfunction, through which it instigates a pro-inflammatory immune response and crystal nephropathy. Maintenance of fatty acid oxidation is a crucial component of renal metabolic-immune homeostasis, with the AMPK–Echs1 axis serving as a core regulator and a promising therapeutic target for metabolic dysfunction-associated crystal nephropathy.