People with MASLD have an elevated risk of cardiovascular disease, cognitive decline, and other metabolic complications, yet the biological mechanisms connecting these conditions remain incompletely understood. In a new study published in the journal Aging, researchers investigated whether lipocalin-2 (LCN2), a protein involved in inflammatory and metabolic signaling, is associated with early vascular dysfunction, cognitive impairment, and cardiovascular risk in patients with MASLD.
The study was led by co-first authors Gaetano Pacinella from the University of Palermo, and the Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, Palermo, and Alessandro Del Cuore from the same institutions. Gaetano Pacinella also served as the corresponding author.
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At present, LCN2 should be primarily considered a marker of systemic inflammatory burden and disease severity, and its potential as a therapeutic target warrants further investigation in mechanistic and interventional studies
Gaetano Pacinella et al.
The investigators conducted a cross-sectional study involving 40 patients with recently diagnosed MASLD and 40 age- and sex-matched control participants without liver disease. They measured circulating LCN2 levels together with endothelial function using the reactive hyperemia index (RHI), myocardial mechano-energetic efficiency (MMEE), and cognitive performance using the Mini-Mental State Examination (MMSE). Compared with controls, patients with MASLD had significantly higher LCN2 concentrations, poorer endothelial function, lower myocardial mechano-energetic efficiency, and lower MMSE scores. Even after adjustment for age, body mass index, and diabetes, MASLD remained independently associated with elevated LCN2 levels, impaired endothelial function, and reduced cognitive performance.
To better understand these associations, the researchers performed additional analyses to determine whether LCN2 itself independently predicted vascular dysfunction or cognitive impairment. Although LCN2 levels were significantly higher in patients with MASLD, the relationships between LCN2 and vascular or cognitive measures were no longer statistically significant after accounting for major cardiometabolic risk factors. These findings suggest that elevated LCN2 primarily reflects the broader metabolic and inflammatory burden associated with MASLD rather than acting as a direct cause of cardiovascular or neurological dysfunction.
The findings also reinforce the concept that MASLD affects multiple organ systems. In addition to liver disease, patients demonstrated evidence of endothelial dysfunction, subtle cardiac functional impairment, and early cognitive changes. The authors suggest that chronic low-grade inflammation, insulin resistance, adipose tissue dysfunction, and vascular injury likely interact to drive these systemic complications, highlighting the importance of evaluating cardiovascular and neurological health alongside liver disease in patients with MASLD.
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“At present, LCN2 should be primarily considered a marker of systemic inflammatory burden and disease severity, and its potential as a therapeutic target warrants further investigation in mechanistic and interventional studies,” the researchers state.
The study also identified endothelial dysfunction as a potentially useful indicator of cardiovascular risk in MASLD. Reactive hyperemia index measurements successfully distinguished patients with MASLD from healthy controls, supporting the value of noninvasive vascular assessment in this population. However, the authors emphasize that the study’s cross-sectional design cannot establish cause-and-effect relationships and that larger longitudinal studies will be needed to determine whether improving metabolic health or reducing systemic inflammation can prevent cardiovascular and cognitive complications.
Overall, this study adds to growing evidence that MASLD should be viewed as a systemic metabolic disease rather than an isolated liver disorder. By linking MASLD with endothelial dysfunction, early cognitive impairment, and increased circulating LCN2 levels, the findings support a more comprehensive approach to patient evaluation. While additional research is needed to clarify the biological role of LCN2 and determine whether these changes can be modified therapeutically, the study highlights the importance of early cardiovascular and neurological risk assessment in patients with MASLD.
Source: Impact Journals LLC
07.08.2026
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