Haikunshenxi capsule alleviates renal fibrosis in chronic kidney disease via modulation of indoxyl Sulfate-Aryl hydrocarbon receptor signaling.

BACKGROUND: Renal fibrosis, a common pathological endpoint in Chronic Kidney Disease (CKD), is closely associated with the accumulation of gut-derived uremic toxins, underscoring the therapeutic relevance of the gut-kidney axis. This study investigated the antifibrotic mechanism of Haikunshenxi Capsule (HKSX), a marine-derived drug, and its principal plant-derived metabolite, fucoidan (FPS), focusing on the Indoxyl Sulfate (IS)-Aryl Hydrocarbon Receptor (AhR) signaling pathway. METHODS: In an adenine-induced CKD rat model, HKSX treatment significantly improved renal function and attenuated tubulointerstitial fibrosis. Targeted metabolomics analysis revealed that HKSX modulated tryptophan metabolism and reduced the systemic IS accumulation. Mechanistically, immunofluorescence and Western blotting revealed that the elevated IS levels were associated with increased AhR nuclear accumulation and subsequent upregulation of Cytochrome P450 enzymes (CYP1A1/CYP1B1) in renal tubular cells. This aberrant signaling activation was associated with Epithelial-Mesenchymal Transition (EMT), characterized by loss of E-cadherin (E-cad) and gain of α-smooth muscle actin (α-SMA). RESULTS: HKSX treatment reduced AhR nuclear accumulation, downregulated CYP expression, and attenuated EMT. In vitro experiments using IS-stimulated HK-2 cells suggested that FPS attenuated activation of this pathway, with effects comparable to those of the specific AhR inhibitor CH223191 on AhR-mediated EMT-related changes. CONCLUSION: In conclusion, HKSX exerts a renal protective effect by reducing systemic uremic toxin accumulation and attenuating IS/AhR signaling-associated EMT, supporting the therapeutic potential of HKSX against renal fibrosis.