Aldehyde dehydrogenase family 6A1 (ALDH6A1) catalyzes the conversion of active aldehydes into corresponding acids, and ALDH6A1 deficiency causes methylmalonic acidemia (MMA), a rare autosomal recessive disorder severely affecting neonatal survival. Hyperlipidemia induced by high-fat diet inhibits ALDH6A1 expression in peri-implant tissue and impairs titanium (Ti) implant osseointegration. However, whether diet-induced hyperlipidemia leads to MMA is still not clear. In this study, diet-induced hyperlipidemia mice with femoral implants and localized ALDH6A1 overexpression via lentiviral injection were applied to detect the changes of ALDH6A1 expression and osseointegration. Primary osteoblasts and ALDH6A1 overexpressed osteoblasts were cultured on Ti surface in normal or high-fat medium. In vivo, hyperlipidemia downregulated ALDH6A1 expression in peri-implant tissues and disrupted adhesion-osteogenesis coupling, yet did not lead to MMA. Localized ALDH6A1 overexpression restored osseointegration while concurrently mitigating oxidative damage and reactivating Wnt/β-catenin pathway. In vitro, ALDH6A1 downregulation initiated a vicious cycle composed of reactive oxygen species (ROS), endoplasmic reticulum stress (ERS), and lipid peroxidation (LPO). While ALDH6A1 overexpression facilitated MDA catabolism, interrupted LPO-ROS-ERS cascade, reshaped cytoskeletal organization and osteogenesis. These findings demonstrate ALDH6A1 as a pivotal therapeutic target for hyperlipidemia-related implant failure, showing first proof that metabolic modulation of lipid peroxidation can functionally restore adhesion-osteogenesis coupling at bone-implant interfaces.
Wang et al. (Sun,) studied this question.