Open Research · Aug 30, 2026
HSPE1 deficiency underlies the crosstalk between metabolic dysfunction‐associated steatotic liver disease and age‐related macular degeneration
By Meng J, Maihemuti A, Yuan Y et al.
Abstract The detrimental impact of liver disease on the age‐related retinopathy has seldom been explored. Here, we investigated the association between metabolic dysfunction‐associated steatotic liver disease (MASLD) and incident age‐related macular degeneration (AMD) and explored potential mechanisms of liver‒eye communication. Utilizing a prospective cohort of 343,547 participants followed over a median of 13.7 years, we identified that MASLD was significantly associated with an increased risk of incident AMD. In a mouse model subjected to a 30‐week high‐fat diet, both MASLD and AMD phenotypes were concurrently manifested. Proteomic analysis identified heat shock protein family E member 1 (HSPE1) as the sole protein consistently downregulated in the liver, plasma, and eye of these mice. Inflammation array and lipidomics indicated a systemic environment characterized by mitochondrial‐related inflammation and phospholipid dysregulation. In a sodium palmitate (PA)‐induced lipid overload model of ARPE‐19 cells, lipid overload led to intracellular lipid accumulation, HSPE1 downregulation, disrupted mitochondrial homeostasis and antioxidant function, and consequently, impaired cell viability. HSPE1 overexpression effectively rescued PA‐induced mitochondrial dysfunction and cell injury. Collectively, our findings suggest MASLD correlates with higher risk of AMD and that HSPE1 deficiency may represent a potential mechanistic link between systemic metabolic dysfunction and retinal degeneration.