In a screen designed to identify novel inducers of autophagy, we discovered that 
STAT3 inhibitors potently stimulate the autophagic flux. Accordingly, genetic 
inhibition of STAT3 stimulated autophagy in vitro and in vivo, while 
overexpression of STAT3 variants, encompassing wild-type, nonphosphorylatable, 
and extranuclear STAT3, inhibited starvation-induced autophagy. The SH2 domain 
of STAT3 was found to interact with the catalytic domain of the eIF2α kinase 2 
EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic 
inhibition of STAT3 stimulated the activating phosphorylation of PKR and 
consequent eIF2α hyperphosphorylation. Moreover, PKR depletion inhibited 
autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like 
palmitate. STAT3-targeting chemicals and palmitate caused the disruption of 
inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2α 
phosphorylation, which facilitates autophagy induction. These results unravel an 
unsuspected mechanism of autophagy control that involves STAT3 and PKR as 
interacting partners.