Purpose <p>A critical event in the disc degeneration process is the breakdown of the extra-cellular matrix regulated by proteases. These proteases are kept in check by inhibitors, most importantly SERPINs. Understanding tissue and cellular expression of SERPINs could provide more insights into their physiological roles in intervertebral disc (IVD) homeostasis.</p> Methods <p>Twelve lumbar IVD NP tissues from each group- brain-dead voluntary organ donors (ND); patients with herniated discs (DH) and degenerated discs (DD) were used in this study. Label-free global proteomics approach was conducted to understand the altered patterns of SERPINs. Validation of SERPINs was performed using immunohistochemical analysis (IHC) and western blotting (WB).</p> Results <p>We identified 21 SERPINs, among which 14 passed stringent cut-off. Comparative analysis revealed that 7 SERPINs namely SERPINA1, SERPINA3, SERPINA5, SERPINA8, SERPINC1, SERPINE2, and SERPING1 were common to all the groups. We noticed that SERPINA4, SERPIND1, SERPINF1, SERPINF2 and SERPINH1 was found common to DH and DD groups and SERPINE1 and SERPINB1 were found unique to ND and DD groups, respectively. Significantly decreased expression levels of SERPINA5 (DD, 0.010), SERPINE2 (DD, 0.028) and SERPING1 (DD, 0.000) were found in DD groups when compared with the ND group.</p> Conclusion <p>Our study documents the altered expression of SERPINs in IVD degeneration. The decreased expression of specific, namely SERPINA5, SERPINE2, and SERPING1, can be one of the possible causes of increased ECM degradation in IVDD. However, further studies need to explore the role of SERPINs as a potential molecular target in preventing ECM degradation.</p>