circLRCH3-FUS interaction stabilizes IFI35 mRNA, inhibiting autophagy and aggravating podocyte pyroptosis in lupus nephritis.

BACKGROUND

Lupus nephritis (LN) can severely compromise kidney function, with podocyte injury recognized as a key pathogenic event. This study aimed to elucidate the role of circular RNA circLRCH3 in LN and to clarify its underlying molecular mechanisms.

METHODS

The expression of circLRCH3 was evaluated in renal tissues and serum samples from LN patients, as well as in human podocyte cells (HPCs) treated with LN-derived immunoglobulin G (LN-IgG). The functional significance of circLRCH3 was examined in vitro and in vivo through its knockdown in LN-IgG-induced HPCs and MRL/lpr lupus-prone mice, respectively. Interactions among circLRCH3, fused in sarcoma (FUS), and interferon-induced protein 35 (IFI35) were explored using RNA immunoprecipitation and RNA pulldown assays. Podocyte pyroptosis and autophagy were analyzed by Western blotting and immunofluorescence.

RESULTS

circLRCH3 was significantly upregulated in both LN patient samples and LN-IgG-induced HPCs. Silencing circLRCH3 in MRL/lpr mice attenuated renal pathological damage and improved renal function. In HPCs, circLRCH3 knockdown suppressed pyroptosis, enhanced autophagy, and increased cell viability. Mechanistically, circLRCH3 was found to bind to FUS, thereby stabilizing IFI35 mRNA. This interaction inhibited autophagy and exacerbated pyroptosis in podocytes.

CONCLUSION

circLRCH3 is upregulated in LN and contributes to podocyte injury by inhibiting autophagy and promoting pyroptosis through the FUS-IFI35 pathway. Thus, targeting circLRCH3 may offer a novel therapeutic approach for LN.