<p>Endoplasmic reticulum (ER) stress is a key pathological mechanism in periodontitis. Our study demonstrates that the periodontitis microenvironment induces ER stress, leading to ER Ca²⁺ efflux via inositol 1,4,5-trisphosphate receptors (IP3R) and subsequent mitochondrial Ca²⁺ overload through the IP3R-GRP75-VDAC1-MCU axis. This disrupts intracellular Ca²⁺ homeostasis and ER-mitochondrial function, resulting in excessive generation of reactive oxygen species (ROS). ROS accumulation induces pathological activation of S-palmitoylation, which amplifies the cascade by enhancing Ca²⁺ transporter activity and establishing a vicious Ca²⁺/ROS cycle. Disrupting this cycle thus presents a promising therapeutic approach. We identify DHHC6 as the specific acyltransferase for the ER Ca²⁺ channel IP3R and β-carotene (β-C) as its natural inhibitor. Therapeutically, β-C suppresses pathological S-palmitoylation, impairs Ca²⁺ transporter activity and restores cellular calcium homeostasis. To enhance its therapeutic delivery, we developed a reactive oxygen species (ROS)-responsive hydrogel (PBTGL) that incorporates β-C-loaded liposomes (L@β-C) and graphene oxide/silver nanoparticles (GO/Ag⁺). PBTGL exerts synergistic antibacterial, anti-inflammatory, and osteo-regenerative effects, resulting in marked amelioration of periodontitis. Thus, PBTGL offers a promising alternative therapeutic strategy for clinical periodontitis management.</p> Graphical Abstract <p></p>