Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

Lupus nephritis (LN), an immune complex-mediated glomerulonephritis, is one of the most severe complications of systemic lupus erythematosus. Current therapeutic regimens for LN mainly involve nonspecific immunosuppressants and biologics targeting immune cells, but these treatments are not always effective and some patients are nonresponsive and susceptible to recurrence. Podocytes are essential for maintaining the glomerular filtration barrier. Injury to and loss of podocytes lead to proteinuria, a hallmark of renal involvement and LN. Podocytes are, therefore, emerging as prospective therapeutic targets for LN. There are numerous mechanisms underlying podocyte malfunction in LN, with autophagy, mitochondrial dysregulation, and programmed cell death being the main processes behind podocyte loss. This review summarizes recent advances in understanding podocyte dysfunction in LN pathogenesis and discusses potential therapeutic interventions targeting podocytes in LN. The molecular mechanism of podocyte injury and death in lupus nephritis, including autophagy, mitochondrial dysfunction, and death (pyroptosis, necroptosis, and ferroptosis).Key pointsimage Podocyte injury and death lead to proteinuria and participate in lupus nephritis disease progression.Autophagy pathways and canonical programmed cell death are implicated in podocyte dysfunction in lupus nephritis.Podocyte-targeted therapies are being developed and are expected to be in clinical use in the future.