YAP1 exacerbates pyroptosis and senescence in nucleus pulposus cells by promoting BNIP3-mediated mitophagy.

Yes-associated protein 1 (YAP1) is a crucial downstream effector of the Hippo pathway that plays a role in regulating inflammation and mitochondrial function. However, whether YAP1 regulates pyroptosis in nucleus pulposus (NP) cells caused by inflammation via mitophagy remains unclear. This study aimed to investigate the effects of YAP1 on the pyroptosis of NP cells induced by LPS. Here, we demonstrated that the protein expression of YAP1 in the NP tissue of degenerative discs was significantly reduced. Next, we found that NLRP3 inflammasome activation in YAP1-overexpressing (YAP1-ov) NP cells was further enhanced in the LPS-induced inflammatory microenvironment. YAP1-ov strongly aggravated inflammation-induced pyroptosis and senescence, but these effects were reversed by the inhibition of BNIP3-mediated mitophagy. However, comparative analysis of the overexpression of YAP1 in normal discs and discs after annulus fibrosus puncture revealed that YAP1-ov accelerated the degeneration of normal discs and attenuated the degeneration of annulus fibrosus punctured discs in vivo. Additionally, YAP1-ov upregulated the expression of TNFAIP3, an anti-inflammatory protective protein, and CLPP, a vital protein in the mitochondrial unfolded protein response, in NP cells. Collectively, the above results revealed that YAP1 exacerbates LPS-induced pyroptosis and senescence of NP cells by promoting BNIP3-mediated mitophagy, which causes disc degeneration. Notably, YAP1-ov mitigated the degeneration of the disc caused by annular needle puncture in vivo, suggesting its potential as a therapeutic candidate foracute IDD injury.