Estradiol mitigates lipid accumulation, oxidative stress, apoptosis, and MAPKs activation in NASH rat model with bilateral orchidectomy

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ID: 327396
2026
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Abstract
Abstract Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and lobular inflammation driven by lipid accumulation, oxidative stress, and apoptosis. Low testosterone levels are associated with increased steatosis risk, particularly in transgender women undergoing feminization. To investigate the effects of estradiol supplementation and its mechanisms involving lipid metabolism, oxidative stress, apoptosis, and mitogen-activated protein kinase (MAPK) signaling (ERK, JNK, and p38) in testosterone-deficient rats fed a high-fat, high-fructose (HFHF) diet. Twenty-one male Sprague-Dawley rats were randomized into three groups (n = 7/group): (i) control (standard diet), (ii) ORX + HFHF (bilateral orchidectomy plus HFHF diet), and (iii) ORX + HFHF + E2 (ORX + HFHF plus oral estradiol, 1.6 mg/kg/day). After 6 weeks, the ORX + HFHF group exhibited the greatest hepatic steatosis, lobular inflammation, hepatocyte ballooning, NAS scores, and Oil Red O staining. Lipid accumulation markers (PLIN2 and Foxa1), oxidative stress markers (MDA, 4-hydroxynonenal, HO-1, and iNOS), and Nrf2 expression were significantly increased versus controls. Testosterone deficiency combined with HFHF feeding induced apoptosis primarily through the intrinsic pathway, evidenced by increased Bax, Bcl-2, caspase-3, and caspase-9, while caspase-8 showed an increasing trend. Estradiol supplementation significantly attenuated NASH pathology by reducing lipogenesis, oxidative stress, and apoptosis, with these effects strongly associated with suppression of all MAPK subtypes. Estradiol mitigates NASH progression in testosterone-deficient rats by modulating lipid metabolism, restoring antioxidant defenses, suppressing intrinsic apoptosis, and inhibiting MAPK signaling. These findings provide mechanistic insight into hormone therapy in transgender women and identify GPER/MAPK signaling as a potential therapeutic target.
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Authors Fatist Okrit, Maneerat Chayanupatkul, Natcha Wanpiyarat, Prasong Siriviriyakul, Duangporn Werawatganon
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Journal PNAS nexus
Year 2026
DOI
10.1093/pnasnexus/pgag279
URL
https://academic.oup.com/pnasnexus/article-pdf/5/9/pgag279/70893284/pgag279.pdf
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