Our group has previously shown an altered aminoacidic homeostasis in the microenvironment of classic Hodgkin`s Lymphoma (HL), due to arginine deprivation, which plays a major role in the immune-escape mechanisms and T-cell anergy induction. To study the metabolic adaptive response to arginine deprivation in vitro, we cultured three HL human cell lines (L428, L540, KMH2) with customized complete media or lacking Arg (R0), supplemented with 10% dialyzed fetal bovine serum, in six independent experiments to collect their global metabolomic analysis by gas chromatography-mass spectrometry (GC/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS) platforms by Metabolon Inc and transcriptome profiling by RNA-seq. Apotpostosis and mitochondrial depolarization were measured by FACS. Findings were validated by qRT-PCR and Western Blot analysis. Gene set enrichment analysis (GSEA) showed deep transcriptome rearrangements in KMH2 and HDMYZ cell lines, involving upregulation of genes required for the unfolded protein response, p53 pathway and networks and proteosome degradation, with a minimal effect on metabolism features, except for the genes involved in lactate metabolism. Arg deprivation caused mitochondrial distress and transcriptional reprogramming, via induction of oxidative stress, affecting the mitochondrial activity, switching from glucose-based metabolism to mitochondrial oxidation of fatty acids, requiring the transfer of fatty acids from lipid droplets to mitochondria. RNA-seq analysis showed that induction of ferroptosis key genes GPX4, TXNRD1 and ACSL4 together with reduced intracellular GSH levels and increased amount of cystine and methionine sulfoxide occurred upon arginine deprivation. The low-energy metabolic state induced by the adaptive response to arg-deprivation posed KMH2-HL cells into a quiescence state, with elevated HMOX1 and HMOX-2 to scavenge the excess ROS with subsequent genome instability as shown by increased γHA2X+/ATM+ cells. In HDMYZ, the increased oxidative stress due to arginine deprivation induced the engagement of the UFMylation pathway. These findings were confirmed in vivo, since in peripheral blood of HL patients we found reduced amount of GSH, glutamine and S-adenosylhomocysteine, citrate, methionine (p<0.001), as detected by HPLC. Taken together, our data suggest how arginine deprivation can regulate lipid trafficking, ferroptosis and UFMylation, novel potential targets to overcome drug resistance in cHL.