Various strategies have been implemented to increase the numbers and potency of Tregs in vivo to reduce the severity of graft rejection [110]. Besides targeting metabolic pathways, some studies have also highlighted that the augmentation of the LKB1 pathway is immensely beneficial in reducing graft rejection, and strategies that could activate the LKB1 pathway might be employed as a future treatment in transplantation settings [96]. Some strategies such as overexpressing LKB1 in lentivirus vectors and then use these vectors to create genetically reprogrammed Tregs and then the adoptive transfer of these modified Tregs would be an attractive strategy to prevent or treat Graft vs Host Disease (GVHD) [111]. It has been established that LKB1 downregulation in Tregs in a GVHD pathological condition and this is significant for targeting LKB1-related pathways to treat GVHD. As demonstrated in that, JQ1 (BET bromodomain inhibitor) (Table 1) enhanced the expression of LKB1, ATG5, and LC3-II genes and resulted in the phosphorylation of AMPK, ULK1, and ATG14 in allografts. This phosphorylation process has been reported to prolong heart allograft survival and inhibits the release of inflammatory cytokines [112], which further supports the role of the LKB1 gene in graft survival. Metabolic manipulation to Tregs and its expansion protocol holds tremendous promise in maintaining Treg-based tolerance during inflammatory disorders. It has been reported that rapamycin (Table 1) causes enhanced cell expansion and Treg stability [113]. In addition, recent progress in chimeric antigen receptors (CARs) technology affects the metabolic properties of Tregs [114-116] and enhance the specificity and functionality of Tregs [35, 117, 118]. It is an indirect strategy to modulate metabolic pathways in a cell-type-specific manner. Thus, future studies should emphasize to use a combination of antimetabolites with tolerance-inducing regimens such as co-stimulatory blockade or LKB1 pathway augmentation or modified Treg adoptive transfer to provide specific and effective long-term graft acceptance.