Lipid metabolism orchestrates liver regeneration: an integrated metabolic network

Liver regeneration is a tightly regulated biological process driven by the dynamic interplay of lipid metabolism, involving spatially and temporally coordinated pathways of synthesis, degradation, and lipophagy. This comprehensive review delineates the pivotal roles of lipid metabolic networks in liver regeneration and highlights their potential for clinical translation. During the priming phase, transient regenerative-associated steatosis (TRAS) serves important physiological roles which provide energy through β-oxidation and supply substrates for membrane phospholipid biosynthesis, with its regulation orchestrated by transcriptional and post-translational mechanisms. In contrast, chronic lipid dyshomeostasis impairs regeneration through mechanisms including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and pro-inflammatory signaling. However, protective lipid-handling processes remain active and play pivotal roles in maintaining cellular homeostasis. Lipophagy-mediated selective degradation of lipid droplets (LDs) releases free fatty acids (FFAs), which mitigate oxidative stress and preserve hepatocellular integrity. Furthermore, the gut-liver axis modulates regeneration through microbiota-derived metabolites and incretin hormones that fine-tune the equilibrium between lipid mobilization and storage. Macrophage polarization-metabolic crosstalk emerges as a critical regulator, whereby PPARγ-driven lipogenic networks in reparative macrophages coordinate growth factor secretion and ER expansion via STAT3 activation. Paradoxically, while moderate TRAS supports regeneration through FFA-mediated histone acetylation and membrane raft signaling, pre-existing steatosis exacerbates ischemia-reperfusion injury via lipid peroxidation and necroptosis. Therapeutic strategies targeting lipophagy-ER stress interactions or gut-liver metabolic crosstalk demonstrate therapeutic potential. Future directions include elucidating dynamic lipid metabolic shifts, targeting gut microbiota-liver interactions, and advancing lipidomics-guided personalized therapies. By integrating mechanistic insights with clinical challenges, this review establishes a framework for understanding the metabolic logic underlying liver regeneration and advancing precision medicine in hepatic repair.