Metabolic dysfunction-associated steatotic liver disease (MASLD, renamed from NAFLD in 2023) is the most common chronic liver disease worldwide, with metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) as its inflammatory progression. Step 1: hepatic steatosis (MASLD) — visceral adiposity + insulin resistance → ↑lipolysis → free fatty acid (FFA) flux to liver → triglyceride accumulation (>5% hepatocyte fat). De novo lipogenesis via SREBP-1c + ChREBP also contributes; insulin resistance fails to suppress hepatic gluconeogenesis. Step 2: hepatocyte lipotoxicity — saturated FFAs + lysophosphatidylcholines + ceramides + free cholesterol drive ER stress (cross-link upr er stress perk ire1 atf6), mitochondrial dysfunction, oxidative stress. Step 3: MASH activation — hepatocyte injury releases DAMPs → Kupffer cell + macrophage activation → TNF-α, IL-1β, IL-6, CCL2 → recruits monocytes; NLRP3 inflammasome activation. Step 4: hepatic stellate cell (HSC) activation — quiescent HSCs → activated myofibroblast phenotype (α-SMA+, type I collagen-secreting) → fibrosis F1 → F2 → F3 → F4 cirrhosis. TGF-β + PDGF + LPS-TLR4 are major HSC activators. Step 5: HCC risk — cirrhosis-derived hepatocellular carcinoma; MASH is now a leading liver-transplant indication. Therapeutics — pharmacological: incretins (semaglutide ESSENCE/REGENERATE-class trials, tirzepatide, retatrutide), THR-β agonist resmetirom (Rezdiffra — first MASH FDA approval 2024), pioglitazone (insulin sensitizer + PPARγ), vitamin E (PIVENS trial), FXR agonists (obeticholic acid — withdrew NASH program), PPARα/δ pan-agonists (lanifibranor, elafibranor — phase 3). Lifestyle: 5–10% weight loss reverses early steatosis; ≥10% reverses some fibrosis. Cross-links: insulin glucose homeostasis (IR upstream), fxr tgr5 bile acid receptor (FXR Rx target), ppar alpha gamma delta (TZD + fibrate Rx), ferroptosis gpx4 lipid peroxidation (hepatocyte lipid peroxidation in MASH).
Organ Systems
digestive
endocrine
cardiovascular
Pathway Steps
visceral adiposity + insulin resistance → ↑hepatic FFA flux + de novo lipogenesis — via ↑lipolysis + SREBP-1c/ChREBP-driven lipogenesis; insulin fails to suppress gluconeogenesis. MASLD (formerly NAFLD) is driven by metabolic overload: insulin resistance and visceral adiposity raise free-fatty-acid flux to the liver and, with hyperinsulinemia and excess sugar, ramp up hepatic de novo lipogenesis. The liver receives more fat than it can export or oxidize — the upstream cause of steatosis.
hepatocyte triglyceride accumulation (>5%) → simple steatosis (MASLD) — via usually asymptomatic; reversible with weight loss. When triglyceride accumulates in >5% of hepatocytes, the result is simple steatosis (MASLD). Triglyceride storage is itself relatively inert and may even be protective — a buffer against more toxic lipids — which is why most steatosis does not progress; the danger is the lipid species, not the fat per se.
lipotoxic species (saturated FFAs, ceramides, free cholesterol) → hepatocyte ER stress + mitochondrial dysfunction — via UPR activation; ROS; lipid peroxidation. Progression depends on lipotoxicity: saturated free fatty acids, ceramides, and free cholesterol (not stored triglyceride) injure hepatocytes by inducing ER stress, mitochondrial dysfunction, and oxidative stress. This lipotoxic injury is the switch from benign steatosis toward steatohepatitis.
hepatocyte injury → DAMP release → Kupffer cell + monocyte activation (MASH) — via NLRP3 + TNF-α + IL-1β; ballooning hepatocytes + inflammatory infiltrate. Injured and dying hepatocytes release DAMPs that activate resident Kupffer cells and recruit monocytes, igniting the inflammation that defines MASH (steatohepatitis). This inflammatory, ballooning-and-injury stage — not steatosis alone — is what drives fibrosis and clinical risk.
TGF-β + PDGF + LPS-TLR4 → hepatic stellate cell activation → myofibroblast — via α-SMA+ collagen-secreting phenotype; fibrosis F1 → F4. Inflammatory and injury signals (TGF-β, PDGF, gut-derived LPS via TLR4) activate hepatic stellate cells, which transdifferentiate into collagen-secreting myofibroblasts. These are the principal source of liver scar — the central effector of fibrosis and the key antifibrotic drug target.
progressive fibrosis → cirrhosis (F4) + portal hypertension + HCC risk — via leading liver-transplant indication; HCC even pre-cirrhosis in MASH. Unchecked fibrosis advances through stages to cirrhosis (F4), bringing portal hypertension, decompensation, and a markedly raised risk of hepatocellular carcinoma. Fibrosis stage — more than inflammation grade — is the strongest predictor of liver-related outcomes, so it anchors prognosis and trial endpoints.