Exploring Negative Feedback Mechanisms in the PTEN-ACE Axis: Application of Electrosorb Hydrogel-Based Gene Delivery for Intervertebral Disc Regeneration

Intervertebral disc degeneration (IDD), along with associated low back pain, stands as a primary cause of disability. The renin-angiotensin-aldosterone system has been linked to IDD; however, the mechanisms underlying this relationship have not been determined. In this study, the role of angiotensin-converting enzyme (ACE), a key synthetase in the system, in IDD and its regulatory mechanism were evaluated. Our findings revealed that downregulating ACE alleviates IDD. Additionally, phosphatase and tensin homolog (PTEN) regulated ACE through tripartite motif-containing 63 (TRIM63)-mediated K48-linked ubiquitination. PTEN dephosphorylated TRIM63, while polo-like kinase 1 (PLK1) phosphorylated TRIM63 at Ser67 and Ser69, two crucial sites for the interaction between ACE and TRIM63. Importantly, this regulatory axis also influenced endoplasmic reticulum autophagy by modulating O-GlcNAc modification, highlighting its significant role in the regulation of IDD. Furthermore, we developed a chitosan-virus electrosorb hydrogel for IDD repair therapy using lentivirus-mediated gene editing. The hydrogel exhibited excellent swelling, degradation, release rates, and biocompatibility. Specific gene editing by the chitosan-virus electrosorb hydrogel could reduce IDD in rats. These findings support the efficacy of modulating the PTEN-ACE pathway and O-GlcNAc modification and the therapeutic value of chitosan-virus electrosorb hydrogels for IDD.