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characterized by the presence of lobular inflammation and hepatocyte ballooning [10,14,16] . A new definition
was also included for patients with “non-abusive” alcohol consumption: metabolic dysfunction- and
alcohol-associated liver disease (MetALD), which refers to individuals with moderate alcohol consumption
(30-60 g per day or 210-420 g per week in men, and 20-50 g per day or 140-350 g per week in
women) [10,14,16,17] . This conceptual refinement has improved the identification of subpopulations with distinct
[17]
prognostic implications, such as the lean-MASLD variant . Mortality rates for both MetALD and ALD are
significantly higher compared to MASLD [17,23-28] .

Cautions regarding the new terminology highlight the potential for overdiagnosis in the MetALD subtype.
Indicators of metabolic dysfunction, such as hypertriglyceridemia and arterial hypertension, may reflect
alterations associated with alcohol intake rather than with metabolic dysfunction itself, potentially affecting
[29]
the assessment of complications risks . Petrie et al., by studying an unselected North American population,
pointed out the importance of considering the effects of arterial hypertension and triglycerides as associated
with moderate alcohol consumption rather than as direct outcomes of increased insulin resistance or
lipotoxicity. This distinction complicates the accurate characterization of the effects across different patient
[29]
subtypes with fatty liver disease, especially when alcohol consumption is self-reported . Ciardullo et al.
reported different mortality rates by subgroup, with the MetALD subtype showing higher mortality rates
compared to MASLD, across all causes of death, as well as in mortality associated with cardiovascular
diseases and cancer .
[30]
In real-life settings, a variety of risk factors, beyond the classic metabolic ones or the high risk of alcohol
consumption, can influence the prognosis in various ways [31-37] . García-Nieto et al. observed a substantially
elevated prevalence of advanced fibrosis concomitant with SLD and MASLD among patients with immune-
mediated inflammatory diseases (IMID) in comparison to controls, despite no significant differences in the
prevalence of SLD and MASLD between the cohorts . Therefore, these authors suggest that independent
[37]
mechanisms or molecules could differentially drive the pathogenesis of IMID compared to control MASLD
cases . In this sense, the role of metabolic and immune-mediated comorbidities, as indicated by García-
[37]
Nieto et al., highlights the need to evaluate these subgroups of patients, especially in relation to the
development of primary hepatic neoplasms . Notably, it is also important to recognize that type 2 diabetes
[37]
mellitus (T2DM) is the risk factor with the greatest impact on the development of MASLD, fibrosis
progression, and HCC [31-35,38] .

The controversy surrounding the broader inclusive capacity of the new MASLD concept, specifically its
failure to accurately reflect medium- and long-term complications, raises the possibility that the dimensions
of metabolic dysfunction that involves conceptual changes may serve as indicators of deeper effects on the
pathophysiology of these diseases, which are still being explored . These effects are becoming increasingly
[39]
apparent in the response to systemic treatments in the population with HCC associated with
NAFLD/MAFLD/MASLD . We could encompass these effects under what might be termed immune
[32]
dysfunction associated with SLD, particularly concerning the tissue microenvironment (both tumor and
non-tumor) .
[40]

CONCEPTUAL EVOLUTION OF CANCER BIOLOGY
[41]
From the earliest descriptions of neoplastic diseases in the Edwin Smith Papyrus (breast tumors) and the
Ebers Papyrus (skin and uterine tumors, among others) to the identification of cancer hallmarks by
[42]
Hanahan and Weinberg at the beginning of the 21st century, the conceptual framework of tumor biology
[43]
has evolved significantly [44,45] . Initially, grounded in the reductionist “clonal genetic model of cancer”, which
focused on the sum of mutations, our understanding has now expanded to encompass the intricate