The IRE1α-XBP1s-NFκB axis controls cell survival and epithelial differentiation under osmotic stress through arachidonic acid metabolism activation
Authors:Leandro Gastón Parra1,5, Cecilia Irene Casali1,5, Dylan Ezequiel Sendyk1,5, Ailén Florencia Salafia1, Sabrina Andrea Flor3,4,6, Silvia Edith Lucangioli2,4,6 and María del Carmen Fernández Tome1,5,*
1 Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Biológicas, Cátedra de Biología Celulary Molecular, Buenos Aires, Argentina. 2 Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Tecnología Farmacéutica, Buenos Aires, Argentina. 3 Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Químicas, Buenos Aires, Argentina. 4 Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Tecnología Farmacéuticay Biofarmacia (InTecFyB), Buenos Aires, Argentina. 5 Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini (IQUIFIB)-Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina. 6 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, Buenos Aires, Argentina.
Keywords:
arachidonic acid, phospholipase A2, cyclooxygenase 2, ER stress, unfolded protein response, osmotic stress, cell differentiation
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Leandro Gastón Parra, Cecilia Irene Casali, Dylan Ezequiel Sendyk, Ailén Florencia Salafia, Sabrina Andrea Flor, Silvia Edith Lucangioli, María del Carmen Fernández Tome (2026). The IRE1α- XBP1s-NFκB axis controls cell survival and epithelial differentiation under osmotic stress through arachidonic acid metabolism activation. Cell Stress 10: 32-48. doi: 10.15698/cst2026.04.317
© 2026 Parra et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Arachidonic acid (AA) metabolism plays a critical role in renal cell osmoadaptation. We recently demonstrated that hypertonicity induces the expression and activation of cytosolic phospholipase A2 (cPLA2). On one hand, AA released by cPLA2 enhances triacylglyceride (TG) synthesis and accumulation. On the other hand, AA is converted into prostaglandins (PG) through cyclooxygenase 2 (COX2) activity. Both processes are required for renal cell survival under osmotic stress. However, the mechanisms by which hypertonicity induces cPLA2 expression remain poorly understood. Given that we previously shown that hypertonicity regulates TG synthesis through the IRE1α-XBP1s branch of the unfolded protein response (UPR), here we examined whether XBP1s regulates the cPLA2-AA-COX2 axis in renal cells subjected to osmotic stress. We found that XBP1s modulates hypertonicity-induced expression of cPLA2 and COX2 by increasing NFκB transcriptional activity. Inhibition of IRE1α impaired normal COX2 degradation and disrupted AA metabolism, leading to a decrease in cell viability and preventing hypertonicity-induced epithelial differentiation. Prostaglandin E2 (PGE2) contributed to cell polarization facilitating adherens junction (AJ) assembly. Together, these findings highlight a central role for the IREα-XBP1s-NFκB signaling axis in coordinating cell stress responses and epithelial differentiation through AA metabolism activation.