Background. Ferroptosis is a type of iron‐dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson’s disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. Methods. Repressor element‐1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT‐PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK‐8, flow cytometry, and transmission electron microscope. The levels of neurons‐related proteins and ferroptosis‐associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR‐494‐3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay. Results. Erastin could dose‐dependently induce neuron injury and ferroptosis of LUHMES cells. miR‐494‐3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin‐induced LUHMES cells. Likewise, miR‐494‐3p inhibition had the opposite effects. We also showed that REST was a target gene of miR‐494‐3p and could repress erastin‐induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR‐494‐3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP‐induced PD mouse model. Conclusion. miR‐494‐3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD.

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K ₂ CO ₃ ) promoted the arylation of acrylamide terminal C(sp ² )-H, affording 34 derivatives. Conversely, sodium tert -butoxide ( t -BuONa) mediated the aryl C(sp ² )-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFR ^T790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a “one substrate–multi reactions–multiple products” strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.