The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Smiriglia, A. et al. Cell Death & Disease. 16: 57. (2025).
doi: 10.1038/s41419-025-07331-7.
Summary of the findings
Summary of the findingsMetabolic-dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC), often associated with metabolic dysfunctions like obesity and insulin resistance. The progression from MASLD to HCC involves chronic inflammation, oxidative stress, and altered growth factor signaling, with a notable male predominance. In this context, estrogens play a protective role by reducing oxidative stress and inflammation, key drivers of MASLD progression to HCC.
Smiriglia et al. demonstrated that estrogens improve redox balance, metabolic status, and mitochondrial function in preclinical liver steatosis models, including hepatocyte-like cells derived from human embryonic stem cells exposed to clinically relevant steatotic-inducing agents. Estrogen treatment reversed the steatotic phenotype, reducing lipid droplet accumulation and oxidative stress via upregulation of mitochondrial thioredoxin 2 (TRX2), an antioxidant player regulated by the estrogen receptor. TRX2 silencing abolished estrogen’s protective effects. Importantly, these findings were validated in a retrospective RNA sequencing analysis of MASLD patient cohorts, confirming the clinical relevance of the molecular mechanisms identified. This study highlights estrogen’s potential role in mitigating MASLD progression and its transition to HCC, providing new insights into sex-related differences in liver cancer risk.
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Future impact
This study suggests that targeting TRX2 activation may provide a novel strategy to manage or even prevent MASLD progression to HCC. Therapeutic approaches that mimic estrogen’s activation of TRX2 could be especially beneficial for men and postmenopausal women, reducing the likelihood of cancer development. Furthermore, these findings open the door to personalized therapies that consider each patient’s hormonal and metabolic profile—such as gender and hormone levels—to optimize protection against liver cancer.
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