System-level multi-omics uncover proteomic, peptidomic, and metabolic remodeling in Microcystin-LR exacerbated chronic kidney disease

Chronic kidney disease (CKD) is increasingly linked to environmental toxins, including the cyanobacterial toxin microcystin-LR (MC-LR), particularly in populations with pre-existing renal injury. We have previously demonstrated that MC-LR promotes CKD, however the full underlying mechanism remains poorly understood. This study investigated how MC-LR exacerbates adenine-induced kidney disease in animal models using an integrative multi-omics approach. Male Sprague-Dawley rats were assigned to four groups: control, MC-LR, adenine, and adenine + MC-LR. Histopathology showed that MC-LR alone caused only mild, focal interstitial inflammation and fibrosis, whereas adenine alone induced granulomatous interstitial nephritis with tubular atrophy and acute tubular necrosis. The most severe lesions were in the co-exposure group, with widespread tubular injury, dense granulomatous inflammation, and extensive interstitial fibrosis. Proteomic analysis revealed distinct clustering and overexpression of Ctss, Wipf3, and Hmgcs2 in kidney tissue from the co-exposure group, together with enrichment of pathways related to DNA repair, p53 signaling, and integrin-HMGB1 complexes. Urinary metabolomics and peptidomics revealed metabolic and peptide signatures associated with CAMKK2 signaling, Farnesyl CoQ10, ferroptosis, and immune activation. Integrative multi-omics analysis demonstrated strong cross-omics correlations, highlighting coordinated oxidative stress, mitochondrial dysfunction, ferroptosis, altered mitophagy, and fibrotic remodeling as key mechanisms of MC-LR-enhanced nephrotoxicity. Together, these findings show that even sub-toxic, environmentally relevant MC-LR exposure can amplify kidney injury through tightly interconnected metabolic and inflammatory networks. This work provides mechanistic insight into cyanotoxin-associated kidney disease and supports the need for stricter monitoring and prevention strategies in regions affected by harmful algal blooms.