Elevated TRIM25 Impairs Poly (ADP‐ribose) Metabolism via PARG Degradation and Mediates Compression‐Induced Intervertebral Disc Degeneration

ABSTRACT Intervertebral disc degeneration (IVDD) is a leading global cause of low back pain, with abnormal mechanical stress being a central contributing factor. However, the molecular mechanisms through which mechanical stress signals are transduced into intracellular pathological responses to drive degeneration remain poorly understood. This study demonstrates that mechanical compression induces DNA damage and triggers parthanatos—a caspase‐independent form of cell death driven by toxic accumulation of poly(ADP‐ribose) (PAR) polymers. Mechanistically, mechanical compression upregulates the E3 ubiquitin ligase TRIM25, which directly binds to and promotes the ubiquitination and degradation of poly(ADP‐ribose) glycohydrolase (PARG), leading to disrupted PAR metabolism and toxic PAR accumulation. Concurrently, TRIM25 targets the DNA repair protein Ku80 for degradation, exacerbating genomic instability and activating the RIG‐I innate immune pathway, thereby inducing the release of inflammatory factors. Thus, under mechanical stress, TRIM25 acts as a key node coordinating DNA damage, cell death, and inflammatory responses, forming a multi‐mechanistic network that promotes IVDD progression. In a rat model of compression‐induced IVDD, restoring PAR homeostasis by targeting the TRIM25–PARG axis significantly attenuated disc degeneration, suggesting the therapeutic potential of targeting this pathway in IVDD.