Estrogen-SAM-M6A axis: a novel mechanism of protection against masld

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Albert Einstein College of Medicine $110,228 on December 8, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the estrogen-SAM-M6A axis as a protective mechanism against metabolic dysfunction-associated steatotic liver disease (MASLD).

The research examines why premenopausal females are protected against hepatic steatosis compared to postmenopausal females and males. The project tests the hypothesis that elevated estrogen in high-fat-diet female mice increases availability of the methyl donor S-adenosylmethionine (SAM) and M6A RNA methylation, creating a synergistic protective mechanism. Preliminary data demonstrate that female mice on high-fat diet maintain higher M6A levels and SAM precursor levels than males, and that several enzymes in the methionine cycle—which generates SAM—are estrogen-dependent. If the estrogen-SAM-M6A axis functions as a unified protective pathway, upregulation of this mechanism could inform targeted therapies for hepatic steatosis.

Performance will occur in Bronx, New York through May 31, 2028. The award is classified as a Project Grant, a standard assistance type for NIH extramural basic and clinical research addressing disease etiology, pathogenesis, prevention, diagnosis, and treatment.

Abstract

IT is well known that premenopausal females are relatively protected against metabolic dysfunction- associated steatotic liver disease (MASLD) compared to postmenopausal females and males. Based on these observations and other preliminary studies, estrogen has been implicated in protecting against hepatic steatosis. However, without understanding the specifics of estrogen function in the liver, no targeted therapies based on this mechanism can be developed. Recently, N6-methyladenosine (M6A) RNA methylation in male mice has been shown to be protective against MASLD, and higher levels of M6A have been associated with decreased lipogenesis and hepatic steatosis. Our data in steatotic high FAT diet (HFD) male mice supports this finding by demonstrating their decreased global M6A levels compared to healthy mice. On the other hand, females on HFD do not develop hepatic steatosis and their M6A levels remain relatively high. Female mice on HFD also display higher levels of the M6A precursor, i.e. S-adenosylmethionine (SAM), compared to HFD males. Furthermore, our experiments show that several enzymes of the methionine cycle, which serves to generate SAM, are estrogen dependent and are higher in females compared to males on HFD. Despite these findings, IT is currently not known if estrogen, SAM and M6A RNA methylation are synergistic components of one mechanism that serves to protect young females on HFD against steatosis. We hypothesize that relatively high levels of estrogen in HFD female mice lead to increased availability of methyl donor SAM and more abundant M6A RNA methylation compared to low estrogen models on HFD. This proposal is significant because, if true, IT would imply that upregulation of this estrogen-SAM-M6A axis might be protective against the development of hepatic steatosis. To test this hypothesis, we will first establish regulation of SAM availability and M6A methylation by estrogen. We will then validate that rescue of SAM is sufficient to rescue global M6A levels, as well as M6A methylation of specific lipogenic genes on HFD. Completion of the proposed experiments will establish a novel estrogen - SAM - M6A axis in the liver, which has strong implications in MASLD protection. While IT is known that estrogen and M6A RNA methylation are protective against hepatic steatosis on a high FAT diet, we do not know whether they are synergetic components of one pathway. My project will answer this question, thereby uncovering a novel biological mechanism that can be utilized as a basis for MASLD treatment in the future.