# Fatty Acid Oxidation Fuels Mitochondrial Respiration to Drive Epidermal Stem Cell Fate and Barrier Regeneration

## TL;DR

Fatty acid oxidation powers mitochondrial activity in skin stem cells, driving their differentiation and the skin's ability to regenerate its protective barrier.

## Contribution

This study identifies fatty acid oxidation as a key metabolic driver of epidermal stem cell differentiation and barrier regeneration.

## Key findings

- Fatty acid oxidation fuels oxidative phosphorylation, which is essential for initiating epidermal differentiation.
- Blocking fatty acid oxidation disrupts skin barrier regeneration and differentiation in both lab and living models.
- FAO provides the energy needed for epidermal cells to commit to differentiation, linking lipid metabolism to skin health.

## Abstract

The skin’s barrier function relies on the epidermis, whose structural integrity is maintained by basal stem cells that continuously renew and differentiate to form the multilayered epidermal architecture. Disruptions in epidermal differentiation underlie numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate the late stages of this process, the molecular events driving the early commitment to differentiation remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation (OXPHOS), is a critical determinant of differentiation initiation. Our findings identify fatty acid oxidation (FAO) as the primary metabolic pathway fueling OXPHOS during this process. Pharmacological and genetic inhibition of FAO, both in vitro and in vivo, disrupts differentiation and compromises the regeneration of the epidermal barrier, causing defective responses to physical insults. Mechanistically, FAO enables ATP production in committed epidermal cells to support the high energy demand of the differentiation process, establishing a direct link between lipid metabolism and epidermal homeostasis. These results uncover a previously unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight FAO as a novel target for therapeutic interventions to restore barrier function in pathological conditions.