# A Global Perspective on Metabolic Dysfunction-Associated Steatotic Liver Disease: From Molecular Mechanisms to Therapeutic Strategy Innovation

**Authors:** Yanhao Qiu, Juan Carlos Laguna, Marta Alegret, Laia Vilà

PMC · DOI: 10.3390/nu18040679 · Nutrients · 2026-02-19

## TL;DR

This review explores the causes and treatment of a liver disease linked to metabolic issues, highlighting how it affects men and women differently and the need for better treatment strategies.

## Contribution

The paper provides a comprehensive overview of MASLD's molecular mechanisms and emphasizes the importance of sexual dimorphism and improved preclinical models.

## Key findings

- MASLD progression involves interconnected pathways like de novo lipogenesis and mitochondrial dysfunction.
- Sexual dimorphism in MASLD is influenced by hormones, genetics, and the microbiome.
- Combination therapies are being prioritized over monotherapies for treating MASLD.

## Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a prevalent global health issue driven by metabolic syndrome, with cardiovascular disease being the leading cause of mortality. This review synthesizes current knowledge on its multifactorial pathogenesis, the impact of sexual dimorphism, and key experimental models. The progression of MASLD involves interconnected pathways including dysregulated de novo lipogenesis, insulin resistance, mitochondrial dysfunction, gut dysbiosis, ferroptosis, and genetic and epigenetic predispositions. These mechanisms not only promote hepatic injury but also accelerate atherosclerosis. Notably, MASLD exhibits significant sexual dimorphism, influenced by physiological differences, sex hormones, genetic factors, and the microbiome. The study of these complex processes relies mostly on dietary-induced animal models, particularly in rats, which effectively recapitulate features of the human disease. Given the multifaceted nature of MASLD, the therapeutic focus is shifting from monotherapies to combination or dual-target strategies. To enable this transition, refinement of preclinical models is essential to better understand and target this complex disorder.

## Linked entities

- **Diseases:** Metabolic Dysfunction-Associated Steatotic Liver Disease (MONDO:0013209), cardiovascular disease (MONDO:0004995), atherosclerosis (MONDO:0005311)
- **Species:** Rattus norvegicus (taxon 10116)

## Full-text entities

- **Genes:** Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 25747] {aka PPAR}, MBOAT7 (membrane bound acylglycerophosphatidylinositol O-acyltransferase MBOAT7) [NCBI Gene 79143] {aka BB1, LENG4, LPIAT, LPIAT1, LPLAT, LPLAT11}, GCH1 (GTP cyclohydrolase 1) [NCBI Gene 2643] {aka DYT14, DYT5, DYT5a, GCH, GTP-CH-1, GTPCH1}, Irs2 (insulin receptor substrate 2) [NCBI Gene 29376] {aka 4PS, IRS-2}, ND6 (NADH dehydrogenase subunit 6) [NCBI Gene 4541] {aka MTND6}, ESR1 (estrogen receptor 1) [NCBI Gene 2099] {aka ER, ESR, ESRA, ESTRR, Era, NR3A1}, SLC40A1 (solute carrier family 40 member 1) [NCBI Gene 30061] {aka FPN, FPN1, HFE4, IREG1, MST079, MSTP079}, HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13) [NCBI Gene 345275] {aka FLDP, HMFN0376, NIIL497, SCDR9, SDR16C3}, KHK (ketohexokinase) [NCBI Gene 3795] {aka FRUCTU}, ADIPOQ (adiponectin, C1Q and collagen domain containing) [NCBI Gene 9370] {aka ACDC, ACRP30, ADIPQTL1, ADPN, APM-1, APM1}, ACLY (ATP citrate lyase) [NCBI Gene 47] {aka ACL, ATPCL, CLATP}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, ACACA (acetyl-CoA carboxylase alpha) [NCBI Gene 31] {aka ACAC, ACACAD, ACACalpha, ACC, ACC1, ACCA}, SERPINE1 (serpin family E member 1) [NCBI Gene 5054] {aka PAI, PAI-1, PAI1, PLANH1}, LOX (lysyl oxidase) [NCBI Gene 4015] {aka AAT10}, MLYCD (malonyl-CoA decarboxylase) [NCBI Gene 23417] {aka MCD}, GIP (gastric inhibitory polypeptide) [NCBI Gene 2695], GCKR (glucokinase regulator) [NCBI Gene 2646] {aka FGQTL5, GKRP}, Rock2 (Rho-associated coiled-coil containing protein kinase 2) [NCBI Gene 19878] {aka B230113H15Rik, ROKalpha, Rho-kinase, Rock-II, Rock2m, mKIAA0619}, SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] {aka HMD, IFAP2, SREBP1, bHLHd1}, APOC3 (apolipoprotein C3) [NCBI Gene 345] {aka APOCIII, Apo-C3, ApoC-3}, Mir511 (microRNA 511) [NCBI Gene 100124488] {aka Mirn511, mir-511, mmu-mir-511}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, SCAP (SREBF chaperone) [NCBI Gene 22937], Pck1 (phosphoenolpyruvate carboxykinase 1) [NCBI Gene 362282] {aka GTP, PCK, PEPCK-C, Pepck, RATPEPCK}, TM6SF2 (transmembrane 6 superfamily member 2) [NCBI Gene 53345], ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, DNASE2 (deoxyribonuclease 2, lysosomal) [NCBI Gene 1777] {aka AIPCS, DNASE2A, DNL, DNL2}, Acly (ATP citrate lyase) [NCBI Gene 24159] {aka ACL, Clatp}, GPT (glutamic--pyruvic transaminase) [NCBI Gene 2875] {aka AAT1, ALT, ALT1, GPT1, SGPT}, PNPLA2 (patatin like domain 2, triacylglycerol lipase) [NCBI Gene 57104] {aka 1110001C14Rik, ATGL, FP17548, PEDF-R, TTS-2.2, TTS2}, GCK (glucokinase) [NCBI Gene 2645] {aka FGQTL3, GK, GLK, HHF3, HK4, HKIV}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, CYCS (cytochrome c, somatic) [NCBI Gene 54205] {aka CYC, HCS, THC4}, GPX4 (glutathione peroxidase 4) [NCBI Gene 2879] {aka GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx}, PLAT (plasminogen activator, tissue type) [NCBI Gene 5327] {aka T-PA, TPA}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, EDN1 (endothelin 1) [NCBI Gene 1906] {aka ARCND3, ET1, HDLCQ7, PPET1, QME}, FGF21 (fibroblast growth factor 21) [NCBI Gene 26291], Gls2 (glutaminase 2 (liver, mitochondrial)) [NCBI Gene 216456] {aka A330074B06Rik, GA, GLS, Lga}, AR (androgen receptor) [NCBI Gene 367] {aka AIS, AR8, DHTR, HPCX3, HUMARA, HYSP1}, GCGR (glucagon receptor) [NCBI Gene 2642] {aka GGR, GL-R, MVAH}, GPR166P (G protein-coupled receptor 166, pseudogene) [NCBI Gene 442206] {aka GPCR, PGR9}, S100A4 (S100 calcium binding protein A4) [NCBI Gene 6275] {aka 18A2, 42A, CAPL, FSP1, MTS1, P9KA}, PRKCE (protein kinase C epsilon) [NCBI Gene 5581] {aka PKCE, nPKC-epsilon}, FAS (Fas cell surface death receptor) [NCBI Gene 355] {aka ALPS1A, APO-1, APT1, CD95, FAS1, FASTM}, Adrb3 (adrenoceptor beta 3) [NCBI Gene 25645] {aka ADRB}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, VCAM1 (vascular cell adhesion molecule 1) [NCBI Gene 7412] {aka CD106, INCAM-100}, Khk (ketohexokinase) [NCBI Gene 25659] {aka KETHPRO}, MSR1 (macrophage scavenger receptor 1) [NCBI Gene 4481] {aka CD204, SCARA1, SR-A, SR-AI, SR-AII, SR-AIII}, SLC2A4 (solute carrier family 2 member 4) [NCBI Gene 6517] {aka GLUT4}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, Pnpla3 (patatin like domain 3, 1-acylglycerol-3-phosphate O-acyltransferase) [NCBI Gene 362972] {aka Adpn}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, METTL3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) [NCBI Gene 56339] {aka IME4, M6A, MT-A70, Spo8, hMETTL3}
- **Diseases:** hepatic lipid (MESH:D011017), necrosis (MESH:D009336), hyperplasia (MESH:D006965), TS (MESH:D014424), glucose intolerance (MESH:D018149), CDD (MESH:D002796), HCC (MESH:D006528), Metabolic Dysfunction (MESH:D008659), visceral obesity (MESH:D056128), hepatic metabolic dysregulation (MESH:D021081), urinary incontinence (MESH:D014549), visceral adiposity (MESH:D007418), nodular hyperplasia (MESH:D020518), hypertriglyceridemia (MESH:D015228), pruritus (MESH:D011537), endothelial (MESH:D005642), adipose (MESH:D018205), NASH (MESH:D005235), obesity (MESH:D009765), HFHCD (MESH:D006937), ALD (MESH:D008108), type 2 diabetes (MESH:D003924), MAFLD (MESH:D005234), MASL (MESH:D017093), De Novo Lipogenesis (MESH:D005862), drug-induced liver injury (MESH:D056486), X chromosome abnormalities (MESH:D002869), Dysbiosis (MESH:D064806), endothelial dysfunction (MESH:D014652), Dimorphism (MESH:D015439), NAFLD (MESH:D065626), CVD (MESH:D002318), IR (MESH:D007333), weight loss (MESH:D015431), liver fibrosis (MESH:D008103), end-stage liver disease (MESH:D058625), thrombotic (MESH:D013927), metabolic disturbances (MESH:D024821), Fibrosis (MESH:D005355), hyperandrogenism (MESH:D017588), iron overload (MESH:D019190), gastrointestinal symptoms (MESH:D012817), endothelial inflammation (MESH:D007249), Liver abnormalities (MESH:D008107), injury (MESH:D014947), ballooning (MESH:D054549), AS (MESH:D050197), Mitochondrial Dysfunction (MESH:D028361), alcoholic (MESH:D000437), cirrhotic (MESH:D000094724), hyperinsulinemia (MESH:D006946), hyperinsulinemic (MESH:D044903), H2S deficiency (MESH:D007153), lipid metabolism disorders (MESH:D052439), hypertension (MESH:D006973), PCOS (MESH:D011085)
- **Chemicals:** 4-HNE (MESH:C027576), mirabegron (MESH:C520025), DAG (MESH:D004075), alcohol (MESH:D000438), sphingolipid (MESH:D013107), BCAAs (MESH:D000597), acetate (MESH:D000085), ROS (MESH:D017382), ceramides (MESH:D002518), hydroxyl radicals (MESH:D017665), SCFA (MESH:D005232), cilofexor (MESH:C000717094), NO (MESH:D009569), Cholesterol (MESH:D002784), ADMA (MESH:C018524), trans fatty acids (MESH:D044242), glucose (MESH:D005947), citrate (MESH:D019343), GSH (MESH:D005978), ATP (MESH:D000255), Fructose (MESH:D005632), tropifexor (MESH:C000630573), retinol (MESH:D014801), OH (MESH:C031356), pemafibrate (MESH:C540740), resmetirom (MESH:C588408), testosterone (MESH:D013739), iron (MESH:D007501), Lipid (MESH:D008055), LPS (MESH:D008070), CDAA (MESH:C009158), FFA (MESH:D005230), cenicriviroc (MESH:C506967), amino acid (MESH:D000596), BH4 (MESH:C003402), Choline (MESH:D002794), BemA (MESH:C581236), coconut oil (MESH:D000074263), polyol (MESH:C024617), selonsertib (MESH:C000654501), lactate (MESH:D019344), carbohydrates (MESH:D002241), MDA (MESH:D008315), fatty acid (MESH:D005227), CoQ10 (MESH:C024989), CA (MESH:D019826), lipid hydroperoxides (MESH:D008054), cholesteryl esters (MESH:D002788), telmisartan (MESH:D000077333), TG (MESH:D014280), TCA (MESH:D014238), BA (MESH:D001647), H2S (MESH:D006862), lard (MESH:C029310), ferrostatin-1 (MESH:C573944), fat (MESH:D005223), Methionine (MESH:D008715), FAO (-), licogliflozin (MESH:C000709456), L-carnitine (MESH:D002331)
- **Species:** Enterobacter (genus) [taxon 547], Nicotiana tabacum (American tobacco, species) [taxon 4097], gut metagenome (species) [taxon 749906], Ruminococcus (genus) [taxon 1263], Mus musculus (house mouse, species) [taxon 10090], Bacteroides (genus) [taxon 816], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Faecalibacterium prausnitzii (species) [taxon 853], Akkermansia muciniphila (species) [taxon 239935], Escherichia coli (E. coli, species) [taxon 562]
- **Mutations:** I148M, rs72613567, rs1260326, C>T, Ser/Thr, G to A, rs641738, rs58542926

## Full text

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## Figures

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## References

220 references — full list in the complete paper: https://tomesphere.com/paper/PMC12943086/full.md

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Source: https://tomesphere.com/paper/PMC12943086