Endoplasmic reticulum stress coordinates perfluorononanoic acid (PFNA)-induced dysfunction in murine preadipocytes.

Perfluorononanoic acid (PFNA), a persistent long-chain per- and polyfluoroalkyl substance (PFAS), is increasingly recognized as a potential metabolic disruptor; however, the cellular and molecular mechanisms underlying its obesogenic activity remain poorly understood. In the present study, we investigated the effects of low nanomolar PFNA concentrations on 3T3-L1 adipocyte differentiation and function, with particular emphasis on the exposure timing during adipogenesis process and the molecular mechanisms underlying PFNA-induced adipose dysfunction. PFNA exposure during the proliferative preadipocyte phase, more than during differentiation period, induced a persistent senescence-like phenotype in fully differentiated adipocytes, characterized by senescence-associated-β- galactosidase activity and an increase inthe p53/p21 checkpoint axis. These effects were accompanied by activation of the unfolded protein response (UPR), as indicated by upregulation of ER stress-associated markers. Early PFNA exposure, also promoted adipogenesis and pro-inflammatory signaling. Interestingly, pharmacological inhibition with tauroursodeoxycholic acid (TUDCA) markedly prevented PFNA-induced cellular dysfunction, identifying ER stress as a key upstream mediator linking PFNA exposure to downstream senescence-like, oxidative, adipogenic and inflammatory alterations. Collectively, these findings identify the proliferative preadipocyte phase as a particularly sensitive window for low-concentration PFNA exposure and suggest that PFNA-induced senescence and ER stress represent interconnected mechanisms contributing to persistent adipocyte dysfunction and its potential obesogenic effects.