cGAS-STING axis activation drove inflammatory phenotype acquisition of senescent nucleus pulposus cells via p65-mediated transcriptional modulation

Given the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socio-economic challenge to the aging population, which is importantly attributed to intervertebral disc degeneration (IVDD), a highly prevalent affliction of aging. Elastic nucleus pulposus (NP) tissue is essential for maintenance of IVD structural and functional integrity. Native NP cells exhibit crucial functions for regulating extracellular matrix homeostasis, constructing an accommodating biomechanical environment and maintaining the gelatinous property of NP tissue. The accumulation of senescent NP cells with inflammatory hypersecretory phenotype due to aging and other damaged factors is a distinctive hallmark of IVDD initiation and progression. In this study, we revealed a mechanism of IVDD progression in which aberrant genomic DNA damage promotes NP cell inflammatory senescence via activation of cGAS-STING axis. cGAS-STING axis activation drove inflammatory phenotype acquisition and inflammatory hypersensitivity to damaged signals of senescent NP cells via p65-mediated transcriptional modulation. And STING pharmacological inhibitor notably suppressed p65-mediated inflammatory response formation and senescence-associated screctory phenotype (SASP) acquisition of senescent cells. The CUT&Tag-seq (Cleavage under targets and tagmentation sequencing) in nucleus pulposus (NP) cells from degenerated and no-degenerated human NP tissues via using specific anti-p65 antibody. The p65-binding CUT&Tag-seq in P8 senescent NP cells after treated with STING pharmacological inhibitor (H-151) or vehicle (DMSO) for 24 hours.