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. Proteomics identified distinct clustering and overexpression of Ctss, Wipf3, and Hmgcs2 in the co-exposure group, alongside 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.

慢性肾脏病（Chronic kidney disease, CKD）与环境毒素的关联日益受到关注，其中包括蓝藻毒素微囊藻毒素-LR（microcystin-LR, MC-LR），该关联在已有肾损伤的人群中尤为显著。我们此前已证实MC-LR可促进慢性肾脏病进展，但其完整的潜在致病机制仍知之甚少。本研究采用整合多组学方法，探究了MC-LR如何在动物模型中加重腺嘌呤诱导的肾脏疾病。实验将雄性斯普拉格-道利（Sprague-Dawley）大鼠分为四组：对照组、MC-LR暴露组、腺嘌呤组以及腺嘌呤+MC-LR联合暴露组。组织病理学检测显示，单纯MC-LR暴露仅引发轻度局灶性间质性炎症与纤维化；单纯腺嘌呤暴露则诱导出肉芽肿性间质性肾炎，伴随肾小管萎缩与急性肾小管坏死；而联合暴露组的病变最为严重，表现为广泛的肾小管损伤、密集的肉芽肿性炎症以及大面积的间质纤维化。蛋白质组学分析发现，联合暴露组中Ctss、Wipf3与Hmgcs2呈现显著聚类与过表达，同时富集了DNA修复、p53信号通路以及整合素–高迁移率族蛋白B1（integrin–HMGB1）复合物相关的信号通路。尿液代谢组学与肽组学分析揭示了与钙/钙调蛋白依赖性蛋白激酶激酶2（CAMKK2）信号通路、法尼基辅酶Q10（Farnesyl CoQ10）、铁死亡（ferroptosis）以及免疫激活相关的代谢与肽类特征。整合多组学分析显示各组间存在较强的跨组学相关性，明确了协同失调的氧化应激、线粒体功能障碍、铁死亡、线粒体自噬异常以及纤维化重塑，这些均为MC-LR增强肾毒性的关键机制。综上，本研究结果表明，即使是环境相关剂量的亚毒性MC-LR暴露，也可通过紧密关联的代谢与炎症网络加重肾脏损伤。本研究为蓝藻毒素相关性肾脏疾病提供了机制层面的科学见解，并支持在有害藻华影响区域实施更严格的监测与防控策略。