Key pathogenetic mechanisms of MASLD: an integrated overview.
| Mechanism | Description | Main mediators/pathways | Systemic implications | References |
|---|---|---|---|---|
| Insulin resistance | Increases lipolysis and FFA flux to the liver | IRS-1/2, Akt, hormone-sensitive lipase | Promotes steatosis, endothelial dysfunction | [19, 22, 33] |
| Lipotoxicity and oxidative stress | Accumulation of ceramides and DAG, mitochondrial dysfunction | ROS, impaired mitophagy | Fibrosis, progressive liver damage | [20, 23, 24] |
| Chronic low-grade inflammation | Activation of innate immunity and cytokine production | TNF-α, IL-6, IL-1β, PRRs | Promotes hepatic and systemic injury | [25, 26, 30] |
| Gut dysbiosis | LPS translocation, TLR4 activation | LPS, TLR4, intestinal permeability | Hepatic fibrosis, systemic inflammation | [27, 28] |
| Hepatic stellate cell activation and fibrogenesis | ECM deposition and fibrosis progression | TGF-β, TIMP-1 | Advanced stages: cirrhosis, carcinoma | [29, 30] |
| Glucagon resistance | Altered amino acid clearance, hyperglucagonemia | Glucagon receptor, urea cycle | Worsens metabolic dysfunction | [31–33] |
| Lipoprotein dysmetabolism | Reduced VLDL secretion, toxic lipid accumulation | ApoB, inefficient VLDL | Accelerated atherosclerosis | [33, 34] |
| FXR receptor dysfunction | Impaired bile acid homeostasis | FXR, SHP | Dyslipidemia, steatosis, inflammation | [35] |
| Endothelial dysfunction | Reduced NO, pro-inflammatory/vasoconstrictive state | eNOS, RAAS, vascular inflammation | Cardiovascular and renal complications | [40, 41] |
DAG: diacylglycerols; ECM: extracellular matrix; FFA: free fatty acids; FXR: farnesoid X receptor; NO: nitric oxide; PRRs: pattern recognition receptors; RAAS: renin–angiotensin–aldosterone system; ROS: reactive oxygen species; SHP: small heterodimer partner.
CA: Writing—original draft, Supervision. RN, FB, KZ, LR, FCS, CC, and LEA: Writing—review & editing. AC: Supervision. All authors read and approved the final version.
Ferdinando Carlo Sasso, who is the Editorial Board Member of Exploration of Medicine, had no involvement in the decision-making or the review process of this manuscript. The other authors declare no conflicts of interest.
Not applicable. This article is a review of previously published literature and does not include original studies involving human participants or animals performed by any of the authors.
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