Reduced p62 levels are associated with the induction of the cancer-associated fibroblast
(CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation
and metabolic reprogramming. However, how p62 is downregulated in the stroma
fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field.
Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a
mechanism involving reduction of the NAD+/NADH ratio, which impairs poly (ADP-ribose) …