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The aryl hydrocarbon receptor (AhR) is a well-known ligand-activated cytoplasmic transcription factor that contributes to cellular responses against environmental toxins and carcinogens. AhR is activated by a range of structurally diverse compounds from the environment, microbiome, natural products, and host metabolism, suggesting that AhR possesses a rather promiscuous ligand binding site. Increasing studies have indicated that AhR can be activated by a variety of endogenous ligands and induce the expression of a battery of genes. AhR regulates a variety of physiopathological events, including cell proliferation, differentiation, apoptosis, adhesion and migration. These new roles have expanded our understanding of the AhR signalling pathways and endogenous metabolites interacting with AhR under homeostatic and pathological conditions. Recent studies have demonstrated that AhR is linked to cardiovascular disease (CVD), chronic kidney disease (CKD) and renal cell carcinoma (RCC). In this review, we summarize gut microbiota-derived ligands inducing AhR activity in patients with CKD, CVD, diabetic nephropathy and RCC that may provide a new diagnostic and prognostic approach for complex renal damage. We further highlight polyphenols from natural products as AhR agonists or antagonists that regulate AhR activity. A better understanding of structurally diverse polyphenols and AhR biological activities would allow us to illuminate their molecular mechanism and discover potential therapeutic strategies targeting AhR activation.