Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 51 min ago
Peer-reviewedCC BYDiabetologia

Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis

  • Amalia Gastaldelli1,2,3
  • Egeria Scoditti4
  • Maria Paula Macedo5,6,7
7 affiliations
  1. 1Centro Interdisciplinare Health Science, Scuola Superiore Sant'Anna, Pisa - UOC, Pisa, Italy. [email protected]
  2. 2Institute of Clinical Physiology, National Research Council, Pisa, Italy. [email protected]
  3. 3UT Health San Antonio, Division of Diabetes, San Antonio, TX, USA. [email protected]
  4. 4Institute of Clinical Physiology, National Research Council, Pisa, Italy
  5. 5APDP - Diabetes Portugal, Education and Research Center, Lisbon, Portugal
  6. 6NOVA Medical School, Faculdade de Ciências Médicas (NMS, FCM), Universidade NOVA de Lisboa, Lisbon, Portugal
  7. 7iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas (NMS, FCM), Universidade NOVA de Lisboa, Lisbon, Portugal
Open at sourcePDFDOICite

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe and aggressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent liver-specific consequences of systemic metabolic dysfunction. This review synthesises current evidence on the metabolic and hormonal determinants of MASLD progression, with a particular focus on the mechanisms linking systemic dysfunction across multiple tissues to hepatic inflammation and fibrosis. MASLD pathogenesis is driven by complex interactions between insulin resistance, impaired glucose metabolism, dysfunctional adipose tissue lipolysis and altered hepatic de novo lipogenesis. Central to this process is the dysregulation of key metabolic hormones, including insulin and glucagon, whose imbalance disrupts both glucose and lipid fluxes, leading not only to hepatic steatosis but also to altered hepatic glucose handling, increased substrate delivery and reduced metabolic flexibility. This promotes lipid accumulation as well as glucotoxic and lipotoxic stress. These metabolic disturbances trigger hepatocellular injury and activate inflammatory signalling pathways, including adipokine-mediated crosstalk between adipose tissue and the liver, promoting hepatic stellate cell activation and ultimately leading to a state of chronic low-grade inflammation (metaflammation) that integrates hepatocyte stress, immune cell activation and hepatic stellate cell-driven fibrogenesis. This review also highlights sex-specific hormonal regulation and the gut-liver-adipose axis as determinants of disease heterogeneity and immunometabolic injury. By integrating mechanistic insights across glucose and lipid metabolism, tissues and hormonal pathways, this review underscores how systemic metabolic dysfunction is translated into progressive liver injury and fibrosis. Understanding these interconnected mechanisms of disease progression is essential for identifying therapeutic targets and advancing mechanism-based and precision medicine approaches for MASLD and MASH.

Related

  1. Prediction Models Versus Fibrosis-4 Index (FIB-4) for Advanced Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Verification-Audited Systematic Review and Meta-Analysis
    Syed Muhammad Hassan Bukhari, Ushna Shahid, Wahhaj Qayyum +3
    CureusPeer-reviewedCC BYFull textGeneral medicineEurope PMC
  2. Determinants of MASLD and liver fibrosis in maintenance hemodialysis: a prospective evaluation of metabolic, nutritional, and volume-related factors.
    Leyla Koc, Caglayan Keklikkiran, Remzi Adnan Akdogan +1
    Diabetology & metabolic syndromePeer-reviewedCC BY-NC-NDFull textEpidemiology & public healthEurope PMCPMC
  3. Longitudinal Changes in Fibrosis Markers: Monitoring Stiffness/Fibrosis Progression and Prognostic Outcomes in MASLD
    Nalda Debsikréo, Nafissatou Leye, Gora Lo +12
    Clinical Gastroenterology and HepatologyPeer-reviewedLicence not statedFull text36 citedEpidemiology & public healthHAL
  4. Effect of hypertension on long-term adverse clinical outcomes and liver fibrosis progression in MASLD
    Xiao-Dong Zhou, Li-You Lian, Qin-Fen Chen +157
    Journal of HepatologyPeer-reviewedCC BYFull text54 citedEpidemiology & public healthHAL
  5. Associations Between Serum Osteocalcin and Metabolic, Nutritional, and Hormonal Status in Male Patients with Chronic Kidney Disease: A Cross-Sectional Study
    BiomedicinesPeer-reviewedCC BYFull textGeneral medicineEurope PMC

Cite

BibTeXRIS
BibTeX
@article{gastaldelli2026metabolic,
  title = {{Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis}},
  author = {Amalia Gastaldelli and Egeria Scoditti and Maria Paula Macedo},
  journal = {Diabetologia},
  year = {2026},
  month = jun,
  doi = {10.1007/s00125-026-06774-7},
  url = {https://doi.org/10.1007/s00125-026-06774-7},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis
AU  - Amalia Gastaldelli
AU  - Egeria Scoditti
AU  - Maria Paula Macedo
PY  - 2026
DA  - 2026/06/20
JO  - Diabetologia
DO  - 10.1007/s00125-026-06774-7
UR  - https://doi.org/10.1007/s00125-026-06774-7
AB  - Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe and aggressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent liver-specific consequences of systemic metabolic dysfunction. This review synthesises current evidence on the metabolic and hormonal determinants of MASLD progression, with a particular focus on the mechanisms linking systemic dysfunction across multiple tissues to hepatic inflammation and fibrosis. MASLD pathogenesis is driven by complex interactions between insulin resistance, impaired glucose metabolism, dysfunctional adipose tissue lipolysis and altered hepatic de novo lipogenesis. Central to this process is the dysregulation of key metabolic hormones, including insulin and glucagon, whose imbalance disrupts both glucose and lipid fluxes, leading not only to hepatic steatosis but also to altered hepatic glucose handling, increased substrate delivery and reduced metabolic flexibility. This promotes lipid accumulation as well as glucotoxic and lipotoxic stress. These metabolic disturbances trigger hepatocellular injury and activate inflammatory signalling pathways, including adipokine-mediated crosstalk between adipose tissue and the liver, promoting hepatic stellate cell activation and ultimately leading to a state of chronic low-grade inflammation (metaflammation) that integrates hepatocyte stress, immune cell activation and hepatic stellate cell-driven fibrogenesis. This review also highlights sex-specific hormonal regulation and the gut-liver-adipose axis as determinants of disease heterogeneity and immunometabolic injury. By integrating mechanistic insights across glucose and lipid metabolism, tissues and hormonal pathways, this review underscores how systemic metabolic dysfunction is translated into progressive liver injury and fibrosis. Understanding these interconnected mechanisms of disease progression is essential for identifying therapeutic targets and advancing mechanism-based and precision medicine approaches for MASLD and MASH.
SN  - 0012-186X
SN  - 1432-0428
ER  -