MASLD Explained: Mechanisms, Global Surge, and Emerging Treatments

MASLD has become the most prevalent chronic liver disease on Earth, affecting an estimated 25–30% of the global adult population and up to 70% of those with type 2 diabetes. Projected models suggest more than 55% of adults worldwide will be affected by 2040, with 20–30% progressing to the more severe metabolic dysfunction-associated steatohepatitis (MASH). The condition carries enormous economic costs—exceeding $100 billion USD annually in direct healthcare expenditures globally—and is now among the leading indications for liver transplantation in Western countries (~20.3% of all transplants).

The review examines how the liver's diverse cell types—hepatocytes, Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells, and cholangiocytes—shift from coordinated healthy function to pathological states driving steatosis, inflammation, and fibrosis. Mitochondrial dysfunction emerges as a critical hub: impaired mitochondria reduce fatty acid oxidation, elevate reactive oxygen species, promote lipid accumulation, and amplify inflammatory signaling, accelerating progression from steatosis to MASH.

Beyond metabolic risk factors (insulin resistance, dyslipidemia, hypertension, obesity), the authors emphasize underappreciated lifestyle drivers. A Western-style diet (high fat, high sugar) remodels gut microbiota—elevating Blautia producta and the metabolite 2-oleoylglycerol—which activates the GPR119/TAK1/NF-κB/TGF-β1 pathway to drive macrophage priming and stellate cell activation. Physical inactivity independently worsens MASLD by reducing mitochondrial biogenesis and increasing lipotoxicity, while short sleep (<5–6 h/night) and circadian disruption (shift work, jet lag) exacerbate hepatic lipid accumulation. Chronic psychological stress further promotes visceral adiposity and hepatic triglyceride synthesis via glucocorticoid release.

On the therapeutic front, the review covers lifestyle interventions (moderate-to-vigorous aerobic exercise 135–240 min/week reduces intrahepatic triglycerides even without weight loss), approved pharmacological agents including the recently FDA-cleared resmetirom (a thyroid hormone receptor-β agonist), and a pipeline of FXR agonists, GLP-1 receptor agonists, SGLT2 inhibitors, and microbiome-targeted strategies. Diagnostic advances including non-invasive biomarker panels and elastography are also reviewed alongside risk stratification frameworks.

The authors conclude that personalized medicine approaches must account for mitochondrial genetics, metabolic phenotype, gut microbiome composition, and lifestyle exposures simultaneously. Preclinical models that faithfully replicate mitochondrial contributions to MASLD are deemed essential for translating mechanistic insights into effective therapies for this heterogeneous disease.