Hydroxychloroquine alleviates renal fibrosis by modulating dendritic cells glycolipid metabolism and its crosstalk with renal tubular epithelial cells.

Chronic kidney disease is largely driven by renal fibrosis (RF), where dendritic cells (DCs) play a key role in renal immunity, exacerbate RF through metabolic reprogramming and interactions with renal tubular epithelial cells (RTECs). Hydroxychloroquine (HCQ), has shown anti-fibrotic potential, but its mechanisms in RF remain unclear. Here, we investigated HCQ's therapeutic effects and underlying immunological pathways in adenine-induced RF mice and lipopolysaccharide -stimulated bone marrow-derived DCs. In vivo, HCQ administration (10/20 mg/kg) significantly attenuated renal histopathological damage, reduced collagen deposition, improved renal function indices (serum creatinine, blood urea nitrogen), and regulated oxidative stress markers (superoxide dismutase/malondialdehyde) levels. HCQ inhibited DCs maturation, enhanced immunosuppressive markers [(programmed death-ligand1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), immunoglobulin-like transcript (ILT)-3], suppressed pro-inflammatory cytokines while elevating anti-inflammatory cytokines both in vivo and in vitro. Ex vivo, HCQ disrupted DCs-RTECs crosstalk, reversing RTECs apoptosis and fibrotic markers [α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β, collagen type I (Col-I)] expression. Metabolically, HCQ suppressed DCs glycolipid metabolism by downregulating glucose uptake, non-esterified fatty acid secretion, and mitochondrial membrane potential, concomitant with altered expression of glycolysis/lipid utilization-related genes. Notably, HCQ reduced phosphorylation of phosphatidylinositol 3-kinase [PI3K (Tyr458)], protein kinase B [AKT (Ser473)], thereby retaining forkhead box O1 (FoxO1) in nucleus and elevated expression of PD-L1 mediated by disturbing the interaction between FoxO1 and PD-L1 to enhance DCs immunosuppressive activity. Rescue experiments with PI3K agonist 740Y-P confirmed the involvement of downstream signaling. Collectively, HCQ alleviates RF by modulating DCs metabolism and impairing DCs-RTECs crosstalk, underscoring its therapeutic promise for RF.