Colorectal　cancer　(CRC)　has　emerged　as　the　third　most　prevalent　and　second　deadliest　cancer　worldwide.　Metabolic　reprogramming　is　a　key　hallmark　of　cancer　cells.　Phosphoglycerate　dehydrogenase　(PHGDH)　is　over-expressed　in　multiple　cancers,　including　CRC.　Although　the　role　of　PHGDH　in　metabolism　has　been　extensively　investigated,　its　effects　on　CRC　development　remains　to　be　elucidated.　In　the　present　study,　it　was　demonstrated　that　PHGDH　expression　was　significantly　up-regulated　in　colorectal　cancer.　PHGDH　expression　was　positively　correlated　with　that　of　the　aryl　hydrocarbon　receptor　(AhR)　and　its　target　genes,　CYP1A1　and　CYP1B1,　in　CRC　cells.　Knockdown　of　PHGDH　reduced　AhR　levels　and　activity,　as　well　as　the　ratio　of　reduced　to　oxidized　glutathione.　The　selective　AhR　antagonist　stemregenin　1　induced　cell　death　through　reactive　oxygen　species-dependent　autophagy　in　CRC　cells.　PHGDH　knockdown　induced　CRC　cell　sensitivity　to　stemregenin　1　via　the　autophagy　pathway.　Our　findings　suggest　that　PHGDH　modulates　AhR　signaling　and　the　redox-dependent　autophagy　pathway　in　CRC,　and　that　the　combination　of　inhibition　of　both　PHGDH　and　AhR　may　be　a　novel　therapeutic　strategy　for　CRC.