Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function.

Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning, which is critical for lysosome fusion with the autophagosome, but is less well studied. Here, we demonstrate that the absence of TMEM55B in murine models accelerates MASLD onset and progression to metabolic dysfunction-associated steatohepatitis (MASH). In cellular models, TMEM55B deficiency enhances incomplete lipophagy, whereby lysosome-lipid droplet interactions are increased, but lysosomal cargo is not fully degraded and/or released, leading to the development of lipid-filled lysosomes (lipolysosomes). Loss of TMEM55B also impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that targeting lipophagy for MASLD therapeutic development should be carefully considered to ensure promotion of the entire lipophagic flux pathway and whether it occurs in the context of mitochondrial dysfunction.