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Autophagy and ribonucleoprotein granules, such as P-bodies (PBs) and stress granules, represent vital stress responses to maintain cellular homeostasis. SQSTM1/p62 phase-separated droplets are known to play critical roles in selective autophagy; however, it is unknown whether p62 can exist as another form in addition to its autophagic droplets. Here, we found that, under stress conditions, including proteotoxicity, endotoxicity, and oxidation, autophagic p62 droplets are transformed to a type of enlarged PBs, termed p62-dependent P-bodies (pd-PBs). p62 phase separation is essential for the nucleation of pd-PBs. Mechanistically, pd-PBs are triggered by enhanced p62 droplet formation upon stress stimulation through the interactions between p62 and DDX6, a DEAD-box ATPase. Functionally, pd-PBs recruit the NLRP3 inflammasome adaptor ASC to assemble the NLRP3 inflammasome and induce inflammation-associated cytotoxicity. Our study shows that p62 droplet-to-PB transformation acts as a stress response to activate the NLRP3 inflammasome process, suggesting that persistent pd-PBs lead to NLRP3-dependent inflammation toxicity. [Display omitted] • p62 droplets are transformed to a type of P-bodies, pd-PBs, under stress conditions • p62 droplet formation drives the nucleation of pd-PBs • pd-PBs serve as platforms to regulate the formation of NLRP3 inflammasomes • pd-PBs promote NLRP3 inflammasome activation Barrow et al. demonstrate that stress conditions convert autophagic p62 droplets to a type of enlarged P-bodies, p62-dependent P-bodies (pd-PBs), via enhanced p62 condensation. pd-PBs recruit the NLRP3 inflammasome adaptor ASC to assemble the NLRP3 inflammasome and induce inflammation-associated cytotoxicity. [ABSTRACT FROM AUTHOR]