Stiff substrate induces nucleus pulposus cell ferroptosis via YAP and N-cadherin mediated mechanotransduction.

Increased tissues stiffness is associated with various pathological processes, such as fibrosis, inflammation, and aging. The matrix stiffness of the nucleus pulposus (NP) tissues increases gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In this study, our results indicated that ferroptosis was involved in stiff substrate-induced NP cell death. Further investigations indicated that the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) increased in NP cells of the stiff group, which mediated lipid peroxidation and ferroptosis in NP cells. In addition, stiff substrate activated the Hippo signaling cascade and induced the nuclear translocation of yes-associated protein (YAP). Interestingly, inhibition of YAP was efficient to reverse the increase of ACSL4 expression caused by matrix stiffness. Furthermore, stiff substrate suppressed the expression of N-cadherin in NP cells. N-cadherin overexpression could inhibit YAP nuclear translocation via the formation of the N-cadherin/β-catenin/YAP complex, and reverse matrix stiffness-induced lipid peroxidation and ferroptosis in NP cells. Finally, the effects of YAP inhibition and N-cadherin overexpression on IDD progression was further illustrated in animal models. Our findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for the treatment of IDD. This article is protected by copyright. All rights reserved.