Mechano-induced arachidonic acid metabolism promotes keratinocyte proliferation through cPLA2 activity regulation

Mechano-induced keratinocyte hyperproliferation is reported to be associated with various skin diseases. Enhanced cell proliferation often requires the active metabolism of nutrients to produce energy. However, how keratinocytes adapt their cellular metabolism homeostasis to mechanical cues remains unclear. Here, we first found that mechanical stretched keratinocytes showed the accumulation of metabolic arachidonic acid by metabolomic analysis. Second, we found that mechanical stretch promoted keratinocyte proliferation through the activation of cytosolic calcium-dependent phospholipase A2 (cPLA2). Knockdown or inhibition of cPLA2 could reduce the release of arachidonic acid and inhibit the proliferation of stretched keratinocytes in vitro and in vivo. Third, by analyzing overlapping transcriptomes of stretched keratinocytes and arachidonic acid-stimulated keratinocytes, we identified the upregulation of hexokinase domain-containing protein 1 (HKDC1) expression, a novel gene involved in glucose metabolism, which was associated with arachidonic acid-induced keratinocyte proliferation during stretching. Our data reveal a metabolic regulation mechanism by which mechanical stretch induces keratinocyte proliferation, thereby coupling cellular metabolism to the mechanics of the cellular microenvironment. Strategies to change the metabolism process may lead to a new way to treat skin diseases that are related to biophysical forces.