Abstract

Cadmium (Cd) exposure induces renal injury by triggering inflammation, cellular senescence, and fibrosis. BMAL1, a core component of the circadian clock, participates in the regulation of cellular stress responses. Lycium barbarum polysaccharide (LBP) and melatonin (MT) possess anti-ageing and anti-inflammatory activities. However, their effect on Cd-induced nephrotoxicity has not yet been elucidated. In this study, wild-type and Bmal1-deficient mice were exposed to Cd for 8 weeks. For protective effect experiments, mice were treated with Cd exposure alone or in combination with LBP and MT. Our analysis revealed that chronic Cd exposure induces renal dysfunction and cellular senescence, accompanied by marked upregulation of BMAL1. Genetic ablation of Bmal1 further aggravated Cd-induced renal injury by increasing Cd accumulation, aggravating mitochondrial dysfunction, enhancing the activation of the NLRP3 inflammasome, senescence pathways, and fibrotic signaling. LBP or MT alone attenuated Cd-induced renal damage, whereas combined administration conferred the most robust protection, improving renal function, preserving mitochondrial homeostasis, suppressing inflammatory activation, alleviating cellular senescence, and reducing collagen deposition. Notably, the protective effects of LBP and MT were associated with modulation of BMAL1 signaling. Together, these data suggest that BMAL1 is an important modulator of Cd-induced inflammatory and senescence responses in the kidney, and demonstrate that LBP plus MT provides superior mitigation of Cd nephrotoxicity.