Aryl hydrocarbon receptor-mediated transcriptional regulation of HSP70 exacerbates endoplasmic reticulum stress in lupus nephritis.

UNLABELLED: Lupus nephritis (LN) is a severe and prevalent complication of systemic lupus erythematosus (SLE), often leading to progressive kidney damage. Endoplasmic reticulum (ER) stress, arising from proteostatic imbalance, triggers the unfolded protein response (UPR) as an initial protective mechanism. However, sustained ER stress can promote apoptosis and exacerbate renal injury, playing a crucial role in the development of LN. The aryl hydrocarbon receptors (AHR), a ligand-activated transcription factor, is involved in immune regulation and stress responses. In this study, we observed AHR protein expression and ER stress markers BiP and CHOP were significantly upregulated in the renal tissues of LN patients and MRL/lpr mice. Pharmacological activation of AHR with 6-formylindolo[3,2-b]carbazole (FICZ), significantly exacerbated disease phenotype in MRL/lpr mice, as evidenced by increased skin lesions, elevated anti-dsDNA antibody levels, and worsened renal pathology including glomerular sclerosis and inflammatory cell infiltration, accompanied by elevated ER stress and apoptosis. Transcriptomic profiling identified HSP70 family main members Hspa1a/b as a key target; while its expression was compensatorily elevated in MRL/lpr mice, FICZ-mediated AHR activation paradoxically suppressed Hspa1a/b levels. Further fcCUT&Tag analysis confirmed that AHR directly binds to the Hspa1a/b locus to regulate the “protein processing in ER” pathway. In vitro, FICZ intensified ER stress-induced apoptosis, whereas HSPA1A overexpression effectively mitigated these effects by modulating the PERK-mediated UPR pathway. In conclusion, our findings demonstrate that AHR activation exacerbates renal injury in LN by transcriptionally inhibiting Hspa1a/b, thereby dismantling a crucial proteoprotective mechanism and fueling maladaptive ER stress. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-026-01547-6.