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bioRxiv · 10.64898/2026.10.21.760790

The MASLD-causing E167K variant of TM6SF2 is degraded by the ubiquitin ligase RNF5

Heidary Arash, E.·Pan, H.·Willenbring, H.
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Abstract

The TM6SF2 E167K loss-of-function variant is one of the most penetrant genetic risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD), including progression to cirrhosis and hepatocellular carcinoma. Here we show that TM6SF2 E167K is recognized and degraded by the ER-associated degradation pathway, and identify RNF5 as the ubiquitin ligase tagging TM6SF2 E167K, providing a rational target for MASLD therapy.

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Heidary Arash, E., Pan, H., Willenbring, H.. 2026-10-23. The MASLD-causing E167K variant of TM6SF2 is degraded by the ubiquitin ligase RNF5. https://doi.org/10.64898/2026.10.21.760790

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