Myricetin ameliorates lupus nephritis by suppressing AXL/PI3K/AKT-mediated B cell proliferation and differentiation

Myricetin (MC) is a natural flavonoid with anti-inflammatory and antioxidant properties that shows protective effects in several renal diseases, yet its specific role in lupus nephritis remains unclear. This study evaluated the therapeutic effect of MC in LN and elucidated its mechanism related to B cell proliferation and differentiation. Using an MRL/lpr mouse model, integrated bioinformatics combining renal transcriptomics, network pharmacology, molecular docking, and machine learning identified the receptor tyrosine kinase AXL as a key target and the PI3K/AKT pathway as the downstream mediator. In vivo, MC treatment significantly reduced lupus activity and kidney damage, as evidenced by decreased proteinuria, autoantibody levels, and immune complex deposition. Mechanistically, MC suppressed renal AXL expression and blocked PI3K/AKT activation, thereby inhibiting abnormal B cell proliferation and plasma cell differentiation. In vitro experiments on primary mouse B cells and Ramos cells confirmed that MC downregulated proliferation markers such as Ki-67 and Ccnd1 as well as differentiation markers including Blimp-1 and Xbp1 via the AXL/PI3K/AKT pathway, demonstrated by CCK-8, EdU, flow cytometry, and Western blot. Collectively, MC alleviates LN by suppressing the AXL/PI3K/AKT axis and restraining pathogenic B cell responses, providing experimental justification for MC as a plant-derived candidate for LN therapy.