Metformin alleviates aging-associated periodontitis via NRF2-mediated restoration of the IRE1α dependent unfolded protein response

Proteostasis disruption due to impaired unfolded protein response (UPR) is a hallmark of aging and contributes largely to cellular dysfunction, but its role and associated mechanisms in aging-associated periodontitis remain unclear. This study reveals that senescent periodontal ligament stem cells (PDLSCs) exhibit impaired NRF2/IRE1α-dependent UPR signaling, leading to increased senescence-associated secretory phenotype (SASP) and reduced osteogenesis. NRF2 overexpression restored IRE1α-dependent UPR signaling and suppressed SASP in senescent PDLSCs, whereas NRF2 knockout/inhibition showed opposite results. Mechanistically, the CUT-RUN assay indicates that NRF2 transcriptionally upregulates IRE1α, thereby restoring UPR activity. Notably, we found that metformin, a known anti-aging agent, attenuated SASP by enhancing NRF2/IRE1α-dependent UPR signaling in PDLSCs. To enhance the therapeutic efficacy of metformin, we developed a senescence-targeted, metformin-releasing nanocomposite hydrogel (TAM-GM@Met) by coating metformin-loaded mesoporous polydopamine nanoparticles with galactose (GM) and encapsulating them within a tannic acid and Ag-MOF-based hydrogel (TAM). This delivery system effectively upregulated NRF2/IRE1α-dependent UPR signaling, suppressed SASP in vitro, and alleviated bone loss in a mouse model of aging-related periodontitis. Our work identifies the NRF2- IRE1α-UPR axis as a critical regulator of PDLSC dysfunction in periodontal aging. We propose TAM-GM@Met-mediated metformin delivery as a promising therapeutic strategy for aging-associated periodontitis by restoring NRF2-regulated IRE1α-dependent UPR signaling. • Aging reduces NRF2 expression and impairs UPR signaling in PDLSCs. • NRF2 alleviates inflammatory senescence by transcriptionally activating IRE1α-mediated UPR signaling. • Metformin restores defective NRF2/UPR signaling in senescent PDLSCs. • TAM-GM@Met specifically targets senescent PDLSCs via SA-β-gal activity for localized metformin delivery. • This delivery system effectively prevents bone resorption in aging periodontitis, providing a promising targeted therapeutic strategy.