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Figure 1. 

Lipotoxicity as a spatially and temporally organized lipid signaling network in hepatocytes. A visual representation of hepatocellular lipotoxicity. Lipid metabolism is presented as a spatially established signaling network controlled by inter-organellar communication. Lipid homeostasis is maintained by contact sites between the endoplasmic reticulum (ER), mitochondria, lipid droplets (LDs), lysosomes, and peroxisomes under physiological conditions, coordinating the synthesis, trafficking, storage, and degradation of lipids. Chronic nutrient excess leads to a dysregulation of this coordination, which results in ER stress, mitochondrial dysfunction, lipid droplet overload, impaired lipophagy, and redox imbalance. These interconnected dysfunctions result in oxidative stress, inflammasome activation, inflammatory signaling, and hepatocellular injury, pointing to lipotoxicity as an emerging consequence of dysregulated lipid signaling and organelle crosstalk. ACSLs, acyl-CoA synthetase long-chain family members; Acyl CoA, acetyl-coenzyme A; ATF4/6, activating transcription factors; CE, cholesteryl ester; Cer, ceramide; eIF2α, eukaryotic initiation factor 2α; ERSE, ER stress response element; FATPs, fatty acid transport proteins; FFAs, free fatty acids; IRE1, inositol-requiring enzyme 1; LPO, lipid peroxidation; mPTP, mitochondrial permeability transition pore; Ox mtDNA, oxidized mitochondrial DNA; PERK, protein kinase R-like ER kinase; SFA, saturated fatty acid; XBP1, x-box binding protein 1.

Figure 2. 

The intracellular lipotoxic signaling network in hepatocytes. Schematic diagram of lipid class-regulated signaling pathways mediating hepatocellular adaptation or lipotoxicity. Elevated saturated fatty acid (SFA) and SFA metabolite levels (e.g., diacylglycerol [DAG], ceramides, lysophospholipids) activate stress and apoptotic signaling cascades (e.g., c-Jun N-terminal kinase [JNK]-mediated pathways, mitochondrial lipoapoptosis [BAX/BAK activation, cytochrome c release, and caspase-3/7 activation]). DAG accumulation promotes PKCε activation and impairs insulin receptor-PI3K-Akt signaling. Ceramides regulate Akt activity by way of PP2A-dependent signaling. At the same time, oxysterols, bile acids (BAs), and lysophospholipids activate receptor-mediated signaling pathways that regulate metabolic and inflammatory programs. Mono-unsaturated fatty acids (MUFAs), which are partially derived from stearoyl-CoA desaturase 1 (SCD1), facilitate triglyceride synthesis and lipid droplet retention, thus alleviating toxic lipid accumulation. AKT, AKT serine/threonine kinase; ERK, extracellular signal-regulated kinase; LPL, lipoprotein lipase; MEK, mitogen-activated protein kinase kinase; MLK3, mixed lineage kinase 3; PI3K, phosphoinositide 3-kinase; PUMA, p53 upregulated modulator of apoptosis; RAC1, ras-related C3 botulinum toxin substrate 1; Raf, Raf kinase; TG, triglyceride.

Figure 3. 

Lipid-driven intercellular crosstalk promotes hepatic inflammation and fibrosis. Schematic illustration of lipid-mediated intercellular communication in the progression from steatosis to MASH. Lipotoxic stress in hepatocytes leads to the secretion of FFAs, cholesterol crystals, damage-associated molecular patterns (DAMPs), and EVs that serve as paracrine signals in the hepatic microenvironment. These signals activate macrophages by using TLRs, especially TLR4, and NLRP3 inflammasome pathways, leading to activation of NF-κB signaling and production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. This inflammatory environment aggravates hepatocyte injury and stimulates HSC activation through TGF-β/Smad signaling pathways, which results in collagen deposition and fibrosis. Systemic lipid signals and gut-derived factors further modulate this pathogenic network. α-SMA, alpha-smooth muscle actin; CE, cholesteryl ester; col1a1, collagen type I alpha 1 chain; col3a1, collagen type III alpha 1 chain; DRs, death receptors; JNK-c, Jun N-terminal kinase; LPC, lysophosphatidylcholine; Smads, mothers against decapentaplegic homologs (SMAD family proteins); TLR3, toll-like receptor 3; TβRI, transforming growth factor beta receptor type I; TβRII, transforming growth factor beta receptor type II.

Figure 4. 

Therapeutic targeting of lipid signaling and trafficking nodes in MAFLD/MASH. Therapeutic approaches are categorized according to the main hepatocellular processes they modify. Blue (upper left) inhibition of lipid signal generation through acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and diacylglycerol acyltransferase 2 (DGAT2) inhibition. Green (upper right), promotion of organelle lipid utilization and mitochondrial function through thyroid hormone receptor β (THR-β) and PPAR pathways. Red (lower left), reduction of inflammatory and fibrogenic signaling through FXR and chemokine pathways. Orange (lower right), modulation of emerging lipid trafficking mechanisms including Niemann-Pick C1 (NPC1), MAMs, and Rho-associated coiled-coil-containing kinase (ROCK) signaling. These complementary interventions reveal targetable nodes that reduce lipotoxic stress, inflammatory amplification, and fibrotic progression. ACC, acetyl-CoA carboxylase; DGAT2, diacylglycerol acyltransferase 2; FASN, fatty acid synthase; PPAR, peroxisome proliferator-activated receptor; THR-β, thyroid hormone receptor beta.

Figure 5. 

The accumulation of toxic lipid species, including SFAs and CERs, in hepatocytes drives key pathological processes. Intracellular lipid excess promotes LD expansion, ER stress, mitochondrial dysfunction, and MAM formation, collectively generating ROS and activating the NLRP3 inflammasome and NF-κB signaling pathways. These events trigger inflammatory responses that are spread beyond the hepatocyte through EV-mediated intercellular communication, promoting macrophage activation and HSC-driven fibrosis. Therapeutic strategies are presented at their respective sites of action: ACC, FASN, and DGAT2 inhibitors reduce toxic lipid generation; THR-β and PPAR agonists enhance mitochondrial lipid utilization; NPC1, MAM, and ROCK inhibitors target intracellular lipid trafficking and organelle stress; and FXR agonists and chemokine receptor inhibitors attenuate downstream inflammatory and fibrogenic signaling.