Category: disease_cascade
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).