Lactate programs PBX1 lactylation and mesangial proliferation in lupus nephritis

Lupus nephritis (LN) constitutes the most common organ-threatening manifestation of systemic lupus erythematosus (SLE), with the pathological proliferation of mesangial cells (MCs) recognized as a critical factor in its pathogenesis and progression. Self-DNA-containing immune complex (DNA-IC) represents a prime pathogenic factor in SLE, yet its pathological impact on MCs remains unclear. In the present study, we elucidated the mechanism underlying the excessive proliferation of MCs following the recognition of DNA-IC in LN patients. Here, we pinpointed that the excessive proliferation of MCs was attributed to an anomalous transition from the G1 to the S phase of the cell cycle in LN patients. Mechanically, the dysfunction of P27 protein resulted in the aberrant G1-S phase transition, and the phenomenon was closely related to the ubiquitin-mediated degradation of its key transcription factor, PBX1. This degradation was regulated by lactylation of PBX1 in the site of Lys40 residue. The elevated lactylation level of PBX1 protein arisen from the up-regulation of glycolysis levels induced by DNA-IC. Accordingly, targeting lactate production in MCs of LN patients effectively alleviated renal inflammation and fibrosis progression in LN patients. Elevated lactate results in PBX1 lactylation, leading to MCs excessive proliferation and thus serving as a promising therapeutic target for LN.