Decreased platelet aggregation and platelet-derived cytokine levels mitigate progressive metabolic dysfunction-associated fatty liver disease

Background
Patients with metabolic syndrome are at high risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), which can progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). MASLD is the most common liver disease and significantly contributes to the cardiovascular disease burden. Enhanced platelet function is linked to steatohepatitis, and antiplatelet therapy may be a potential treatment for progressive MASLD.

Methods
We prospectively analyzed the effect of antiplatelet therapy on hepatic fat, volume, and iron deposition using magnetic resonance imaging (MRI) at baseline and six-month follow-up (Figure 1A). Ex vivo platelet function and plasmatic cytokine levels were assessed to explore pro-inflammatory metabolic dysfunction in MASLD patients (n=51) allocated to dual (DAPT), single (SAPT), or no antiplatelet therapy (naïve) (Figure 1A).

Results
Antiplatelet therapy significantly reduced platelet function (Figure 1B) and was associated with dynamic changes in hepatic volume, fat content, and iron deposition (Figure 1C). Decreased platelet aggregation was directly linked to reduced hepatic volume and iron accumulation (Figure 2A&B). Enhanced platelet function was significantly correlated with increased hepatic fat content, iron deposition, and liver volume (Figure 2C-F). Progressive liver steatosis was linked to dyslipidemia (Figure 3A), while antiplatelet therapy was significantly associated with decreased hepatic low-density lipoprotein (LDL) levels (Figure 3B&C). Elevated concentrations of platelet-derived chemotactic cytokines promoted hepatic steatosis (Figure 3D-F). Additionally, platelet-derived profibrotic, inflammatory, and apoptotic mediators, as well as a distinct cytokine profile, were associated with morphological features of progressive MASLD (Figure 4A-C). In contrast, antiplatelet therapy reduced chemotactic signaling, potentially slowing MASLD progression in metabolic syndrome patients (Figure 4D-F).

Conclusions
This study demonstrates that reduced platelet function attenuates progressive steatosis. Antiplatelet therapy decreased pro-inflammatory and pro-fibrotic chemokine signaling, which was associated with MASLD morphology. Notably, significant reductions in platelet function following antiplatelet therapy correlated with decreased hepatic steatosis, inflammation, and improved dyslipidemia. Assessing platelet function and cytokines could provide insights into MASLD pathophysiology and identify potential platelet-derived biomarkers. Antiplatelet therapy may thus offer beneficial effects on steatosis and help reduce cardiovascular risk in patients with MASLD and metabolic syndrome.