Telitacicept alleviates IgA nephropathy by targeting PDHA1 lactylation to inhibit B cell metabolic reprogramming and lactate-mediated renal injury.

Abstract

Background: Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis, is driven by galactose-deficient IgA1 (Gd-IgA1) production from autoreactive B cells. Current therapies inadequately target core pathogenic mechanisms. Telitacicept (a recombinant fusion protein inhibiting BLyS/APRIL) shows clinical promise, but its molecular mechanisms in modulating B cell metabolism and lactylation-mediated pathways remain unclear.

Methods: IgAN patients and healthy controls were enrolled; B cells were isolated for metabolic flux analysis (OCR/ECAR), lactylation assays (IP/WB/LC-MS/MS), and PDH activity tests. Patients received Telitacicept (160 mg/week) or placebo. Murine IgAN models were established and Telitacicept (1 or 5 mg/kg) was administered. Co-cultures of IgAN patient B cells and human mesangial cells (HMCs) assessed lactate's role in renal injury. Site-directed mutagenesis (PDHA1-K336R) and siRNA knockdown (SIRT3/PDHA1) validated functional mechanisms.

Results: IgAN patient B cells exhibited hyperlactylation of PDHA1 at lysine 336 (K336la), which suppressed pyruvate dehydrogenase (PDH) activity, elevated lactate production, and drove metabolic reprogramming toward glycolysis. This promoted IgA1 secretion and renal dysfunction. Telitacicept, a dual BAFF/APRIL inhibitor, significantly reduced PDHA1-K336la levels, restored PDH activity and OXPHOS, and suppressed lactate/IgA1 production. Mechanistically, Telitacicept upregulated the mitochondrial deacylase SIRT3, which directly bound PDHA1. SIRT3 knockdown abolished Telitacicept's effects. Critically, lactate from IgAN B cells triggered HMC inflammation, fibrosis, and apoptosis, effects reversed by Telitacicept but restored by exogenous lactate. In vivo, Telitacicept dose-dependently attenuated renal injury, fibrosis, and mortality in IgAN rats, while PDHA1 depletion exacerbated B cell metabolic dysfunction and renal damage.

Conclusion: Telitacicept confers renoprotection by inducing SIRT3-dependent PDHA1 delactylation to reverse metabolic reprogramming in IgAN. Targeting the PDHA1 lactylation-SIRT3 axis represents a novel therapeutic strategy for IgAN and related autoimmune disorders.