STAT3 drives the expression of ACSL4 in acute kidney injury
Virginie Poindessous,
Helene Lazareth,
Gilles Crambert,
Lydie Cheval,
Julio L. Sampaio,
Nicolas Pallet
Affiliations
Virginie Poindessous
Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, Paris, France
Helene Lazareth
Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, Paris, France; Université Paris-Cité, Paris, France; Laboratory of Renal Physiology and Tubulopathies, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France
Gilles Crambert
EMR 8228 Metabolism and Renal Physiology Unit, CNRS, Paris, France; CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, Paris, France
Lydie Cheval
EMR 8228 Metabolism and Renal Physiology Unit, CNRS, Paris, France; CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, Paris, France
Julio L. Sampaio
CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, Paris, France
Nicolas Pallet
Laboratory of Renal Physiology and Tubulopathies, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France; Department of Clinical Chemistry, Assistance Publique Hôpitaux de Paris, Georges Pompidou European Hospital, Paris, France; Corresponding author
Summary: Long-chain acyl-CoA synthetase family 4 (ACSL4) metabolizes long-chain polyunsaturated fatty acids (PUFAs), enriching cell membranes with phospholipids susceptible to peroxidation and drive ferroptosis. The role of ACSL4 and ferroptosis upon endoplasmic-reticulum (ER)-stress-induced acute kidney injury (AKI) is unknown. We used lipidomic, molecular, and cellular biology approaches along with a mouse model of AKI induced by ER stress to investigate the role of ACSL4 regulation in membrane lipidome remodeling in the injured tubular epithelium. Tubular epithelial cells (TECs) activate ACSL4 in response to STAT3 signaling. In this context, TEC membrane lipidome is remodeled toward PUFA-enriched triglycerides instead of PUFA-bearing phospholipids. TECs expressing ACSL4 in this setting are not vulnerable to ferroptosis. Thus, ACSL4 activity in TECs is driven by STAT3 signaling, but ACSL4 alone is not enough to sensitize ferroptosis, highlighting the significance of the biological context associated with the study model.
