<p>Parkinson's disease (PD) is a typical neurodegenerative disorder characterized by the aggregation of pathological α-synuclein. The accumulation of misfolded proteins can induce severe endoplasmic reticulum stress (ERS) and lead to neuronal damage. In this study, we investigated the effects of phosphodiesterase 4 (PDE4) inhibitors on ER homeostasis in a PD model. In vitro experiments using SH-SY5Y cells demonstrated that treatment with 1-methyl-4-phenylpyridinium ion (MPP⁺) effectively induced ERS and cellular damage. In contrast, PDE4 inhibition significantly reduced the expression of key ERS markers, including G protein-coupled receptor 78 (GPR78) and C/EBP homologous protein (CHOP), and promoted cell survival. Mechanistically, PDE4 inhibition facilitated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), leading to the upregulation of heme oxygenase-1 (HO-1) and activation of the antioxidant pathway, which effectively alleviated MPP⁺-induced ERS and neuronal damage. In a mouse PD model, administration of the PDE4 inhibitor roflupram (ROF) significantly activated the antioxidant pathway. This was accompanied by improved motor coordination, demonstrating the neuroprotective effects of ROF. These findings suggest that PDE4 inhibition may represent a promising therapeutic strategy for PD.</p> Graphical Abstract <p>The aggregation of pathological α-synuclein triggers intracellular oxidative stress, which leads to endoplasmic reticulum stress (ERS) and exacerbates the accumulation of misfolded proteins and oxidative stress. In contrast, inhibition of phosphodiesterase 4 (PDE4) promotes nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase-1 (HO-1). This pathway alleviates both oxidative stress and ERS, and ultimately provides neuroprotection against neurodegenerative conditions.</p> <p></p>