PTPN22 as a therapeutic target in intervertebral disc degeneration: Modulating mitophagy and pyroptosis through the PI3K/AKT/mTOR axis

• PTPN22 is upregulated in degenerative nucleus pulposus (NP) cells during intervertebral disc degeneration (IDD) progression. • PTPN22 deficiency enhances mitophagy and protects against mitochondrial dysfunction. • PTPN22 suppression reduces pyroptosis and extracellular matrix (ECM) degradation in IDD. • The protective effects of PTPN22 deficiency are mediated through the PI3K/AKT/mTOR signaling pathway. • PTPN22 knockdown significantly slows IDD progression in a puncture-induced rat model, suggesting its potential as a therapeutic target. Intervertebral disc degeneration (IDD) is a predominant risk factor for low back pain (LBP). However, the mechanisms underlying IDD progression remain unclear. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with various chronic inflammatory and autoimmune conditions. However, its role in the progression of IDD remains obscure. This investigation delves into the function of PTPN22 within IDD and examines its molecular mechanisms. The expression levels of PTPN22 in human and rat degenerative nucleus pulposus (NP) cells were analyzed using Western blot and immunohistochemistry. Following PTPN22 knockdown via lentiviral transfection, pyroptosis, extracellular matrix (ECM) degradation, mitophagy, and mitochondrial function were assessed using Western blot, immunofluorescence, Calcein-AM/PI staining, qPCR, Seahorse, JC-1, and MitoSOX assays. The roles of autophagy and the PI3K/AKT/mTOR pathway were further investigated using the autophagy inhibitor 3-MA, Baf-A1, and the PI3K agonist 740Y-P. A puncture-induced rat model was established, and the effects of LV-shPTPN22 on IDD were evaluated through imaging and histological analyses. We noted an upregulation of PTPN22 in degenerative NP cells. A deficiency in PTPN22 was found to enhance mitophagy, thereby alleviating hydrogen peroxide (H 2 O 2 )-induced mitochondrial dysfunction and consequently mitigating NP cell pyroptosis and ECM degradation. Inhibition of the PI3K/AKT/mTOR pathway appears to play a pivotal role in the protective effects of PTPN22 deficiency against IDD. Experiments conducted in vivo revealed that PTPN22 knockdown significantly curtails the progression of IDD. In summary, PTPN22 knockdown alleviates IDD progression by reducing pyroptosis and ECM degradation through enhanced mitophagy. This highlights PTPN22 as a critical contributor to IDD and a promising therapeutic target.