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Page 4 of 7 Lonardo. Metab Target Organ Damage 2024;4:7 https://dx.doi.org/10.20517/mtod.2023.56

PUTATIVE PATHOMECHANISMS INVOLVED
The study by Crudele et al. raises two research questions: why is the female genital tract so susceptible to
carcinogenesis in the setting of dysmetabolic dysfunction? What is the specific role of hepatic fibrosis in the
development of gynecological cancers? [16]

Metabolism and reproduction in women
Probably, the best answer to the first question derives from the observation that metabolism is strictly
[19]
involved during pregnancy and lactation . This tight involvement supports the logical expectation that the
functional collaboration between the female genital tract and metabolism may turn dysfunctional whenever
long-standing metabolic dysfunction occurs. In other words, insulin resistance, oxidative stress associated
with chronic excess of nutrients, and subclinical, long-lasting inflammatory state could conceivably trigger
all the steps involved in the initiation, growth, and diffusion of gynecological cancers . Supporting this
[11]
notion, Lin et al., in their retrospective analysis of 725 consecutive patients with endometrial cancer, found a
strong association between MAFLD and cervical stromal involvement [OR = 1.974, 95% confidence interval
[20]
(Cl) = 1.065-3.659, P = 0.031], which, in its turn, is a predictor of overall survival .
Liver fibrosis
Regarding the second research question, more advanced stages of liver fibrosis might merely identify more
severe or more prolonged metabolic dysfunction. Additional mechanistic explanations involve risky genetic
[21]
polymorphisms, as recently reported by Tai et al. , and gut dysbiosis and altered composition of bile salts
cannot be neglected . A robust body of evidence also suggests that environmental, workplace, and
[18]
household pollution may be a shared risk factor contributing, on the one hand, to NAFLD/MAFLD and, on
the other hand, specifically to gynecological cancers.

Pollution and NAFLD/MAFLD
Environmental pollution may contribute to NAFLD/MAFLD initiation and advancement via different
pathogenic routes comprising (1) the endocrine-metabolic pathway, for example, by inducing
hypothyroidism, and signaling-disrupting chemical hypotheses; (2) interaction of chemicals with
nutrients [22-24] .

In humans, with women being more sensitive to these harmful impacts than men, environmental
contaminants, such as perfluorinated alkyl substances (PFAS), may contribute to NAFLD development and
[25]
progression via altered bile acid profiles and perturbed homeostasis of triacylglycerols and ceramides .
Moreover, pesticides and other phytopharmaceuticals are pro-oxidant compounds, which may intervene in
the pathogenesis of NAFLD via either increased production of reactive oxygen species (ROS), or interaction
(therefore acting as endocrine disrupting chemicals), with various nuclear receptors involved in hepatic
metabolic pathways .
[26]
Microplastics can induce profound perturbation in the hepatic immunological micromilieu and induce
hepatic fibrosis via the recruitment of Vsig4+ macrophages . A large epidemiological study from the UK
[27]
biobank, involving approximately half a million individuals, has suggested that air pollution scores were
positively associated with the odds of higher liver fibrosis scores and new-onset severe liver disease and that,
in agreement, residential greenspaces showed an inverse association with these hepatic outcomes . A
[28]
clinical study from Italy found that workplace toxicant exposure was strongly associated with metabolic
dysfunction-associated steatotic liver disease (MASLD) complications, suggesting that occupational
exposure may be a risk factor for the progression of fibrosis in MASLD .
[29]