Functional Lignin with Enhanced Aliphatic Hydroxyl and Carboxyl Groups to Attenuate Osteosarcoma Progression via Promoting Mitochondrial Dysfunction

Lignin, a complex biopolymer, has promising biomedical applications due to its unique structure and chemical modifiability. This study shows that lignin modified with hydroxyl and carboxyl groups enhances GSH adsorption, thereby improving cytotoxicity and selectivity against osteosarcoma. The modified lignin induces mitochondrial dysfunction via mPTP activation, resulting in membrane depolarization, cytochrome c release, and ATP depletion, ultimately triggering the pro-apoptotic protein BAX and downregulation of the antiapoptotic protein BCL2. Moreover, lignin treatment significantly increased reactive oxygen species (ROS) levels while depleting intracellular GSH, further promoting oxidative stress-induced apoptosis. In vivo studies confirmed that lignin samples were effective in inhibiting tumor growth with a favorable biosafety profile. Among them, CML showed the strongest anticancer effect. These findings highlight the potential of modified lignin as a safe and effective therapeutic agent for OS treatment, offering a novel strategy to enhance oxidative-stress-mediated tumor cell apoptosis while sparing normal cells.