Oleoylethanolamide and palmitoylethanolamide synergize with IFNβ to potentiate apoptosis and PD-L1 induction in SH-SY5Y neuroblastoma cells

Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous bioactive lipids that act as selective agonists of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor implicated in lipid metabolism, inflammation, and cancer biology. While their anti-tumour potential has been suggested in various malignancies, their role in human neuroblastoma (NB) remains unexplored. NB, a paediatric solid tumour with poor prognosis in aggressive forms, may benefit from novel therapeutic strategies that exploit molecular vulnerabilities and enhance the efficacy of existing treatments. Type I interferons (IFNs), particularly IFNβ, are cytokines with well-characterized antiviral and anti-proliferative actions and documented capacity to trigger apoptosis in tumour cells, including NB. In this study, we investigated whether OEA and PEA could modulate IFNβ-induced responses in human SHSY5Y NB cells. Through a combination of viability assays, scratch wound healing, clonogenic assays, and western blotting, we show that OEA and PEA significantly enhance IFNβ-mediated cytotoxicity. Co-treatment with IFNβ and either lipid potentiated apoptosis, as indicated by increased cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP), together with reduced levels of survivin, a protein involved in anti-apoptotic regulation. Importantly, this effect occurred without amplifying canonical IFNβ signalling through the JAK-STAT pathway or PKR induction, suggesting a parallel and complementary apoptotic mechanism. Furthermore, OEA and PEA enhanced IFNβ-induced PD-L1 expression both in whole-cell lysates and on the plasma membrane. Pharmacological inhibition and the genetic silencing of PPARα attenuated PARP cleavage and PD-L1 upregulation, confirming the receptor’s contribution to the observed effects. Collectively, our findings demonstrate that OEA and PEA potentiate IFNβ-induced apoptosis in SH-SY5Y cells through PPARα-dependent mechanisms that synergize with, but remain9 distinct from, classical IFN signalling. This synergism promoting apoptotic cell death while modulating PD-L1 expression, highlights a novel interplay between lipid signalling and cytokine pathways in NB. These results open avenues for further studies aimed at evaluating OEA and PEA as adjuvants in IFN-based therapies and raise the possibility that combining bioactive lipids with immunomodulatory cytokines could improve therapeutic efficacy against NB and other IFN-sensitive malignancies.