The multifaceted role of SQSTM1/p62 in disc degeneration: A master regulator of cellular stress responses

Intervertebral disc degeneration (IDD) is a key contributor to lumbar degenerative diseases and chronic low back pain. Accumulating evidence indicates that Sequestosome 1 (SQSTM1/p62), a multifunctional adaptor protein, plays a pivotal role in IDD pathogenesis through its regulation of autophagy, oxidative stress, inflammation, and programmed cell death. This review summarizes the multifaceted functions of SQSTM1 in the context of IDD, including its involvement in the autophagy-lysosome pathway, antioxidant defense via the Keap1-Nrf2 axis, activation of the NF-κB signaling and NLRP3 inflammasome, and modulation of apoptosis, pyroptosis, and ferroptosis. Moreover, SQSTM1 contributes to extracellular matrix degradation by upregulating matrix metalloproteinases and downregulating their inhibitors. Given its dynamic expression during disc degeneration, SQSTM1 holds promise as both a biomarker for IDD progression and a therapeutic target. Potential strategies targeting SQSTM1 include the use of autophagy inducers, inflammatory pathway inhibitors, and ferroptosis/pyroptosis modulators. However, challenges remain in precisely modulating SQSTM1 activity and translating findings into clinical therapies. Future research leveraging advanced technologies such as single-cell RNA sequencing, proteomics, and organoid models is essential to unravel the complex, stage- and cell-specific roles of SQSTM1 in IDD. Understanding these mechanisms may open new avenues for effective treatment and improved patient outcomes in degenerative spinal disorders.