Altogether, our results suggest that inhalation treatment of rGBM patients with POH mitigate the detrimental effects of global gDNA hypomethylation on tumor cell proliferation while fostering normalization of the MTHFR-mediate one-carbon folate metabolism in patients with recurrent glioblastoma harboring mutant variants for rs1801133 polymorphism. Here, MTHFR is linked to glioblastoma.