MSCs overexpressing FGF21 alleviate acetaminophen-induced acute liver injury by eliciting macrophage-mediated phagocytosis.

BACKGROUND: Acetaminophen (APAP) is a widely used analgesic and antipyretic agent that is safe at therapeutic doses. However, due to its extensive misuse, APAP-induced liver injury has become a major public health concern. Although mesenchymal stem/stromal cells (MSCs) represent a promising emerging therapy for APAP-induced liver injury, considerable research has focused on enhancing their efficacy, notably through genetic modification. Fibroblast growth factor 21 (FGF21), an endocrine hormone activated by metabolic stress, is known to regulate energy homeostasis, glucose and lipid metabolism, and to promote the homing of MSCs to sites of injury. Consequently, this study was designed to determine whether genetically engineering MSCs to overexpress FGF21 (FGF21-MSCs) augments their therapeutic potential against APAP-induced acute liver injury (ALI). METHODS: In this investigation, MSCs were employed as a platform for FGF21 gene delivery. The MSCs were transduced with lentiviral vectors encoding the FGF21 gene to facilitate sustained FGF21 overexpression. We subsequently assessed the therapeutic potential of these FGF21-MSCs in a murine model of APAP-induced ALI. The extent of liver injury was comprehensively evaluated. Furthermore, the underlying mechanisms were elucidated using techniques including immunohistochemistry, immunofluorescence, and flow cytometry. RESULTS: Our results demonstrated that FGF21-MSCs significantly enhanced the therapeutic efficacy of conventional MSCs against APAP-induced ALI via a biphasic mechanism: attenuating oxidative stress and inflammation during the acute injury phase, while actively fostering tissue repair during the subsequent regenerative phase. This protective effect is primarily mediated through the enhancement of macrophage phagocytic capacity, thereby accelerating tissue repair and regeneration. CONCLUSIONS: Our findings demonstrate that FGF21-MSCs significantly augment therapeutic efficacy against APAP-induced ALI in mice, thereby yielding critical insights and revealing novel therapeutic targets for ALI prevention and treatment.