The study investigates the mechanisms by which silica and aluminum salt crystals activate the NALP3 inflammasome, a key player in inflammatory responses. Silica crystals, known to cause inflammation and silicosis, were found to activate the NALP3 inflammasome through phagocytosis, leading to lysosomal damage and rupture. This activation requires lysosomal acidification and the cysteine protease cathepsin B. The authors demonstrate that crystal-independent lysosomal damage, such as that induced by hypertonic solutions or the lysomotropic reagent L-leucyl-L-leucine methyl ester, also activates the NALP3 inflammasome. These findings suggest that the NALP3 inflammasome senses lysosomal damage as an endogenous danger signal, leading to the activation of inflammatory cytokines and recruitment of immune cells. The study highlights the role of lysosomal function in crystal-induced inflammation and provides insights into the mechanisms underlying silica crystal-induced lung inflammation and fibrosis.The study investigates the mechanisms by which silica and aluminum salt crystals activate the NALP3 inflammasome, a key player in inflammatory responses. Silica crystals, known to cause inflammation and silicosis, were found to activate the NALP3 inflammasome through phagocytosis, leading to lysosomal damage and rupture. This activation requires lysosomal acidification and the cysteine protease cathepsin B. The authors demonstrate that crystal-independent lysosomal damage, such as that induced by hypertonic solutions or the lysomotropic reagent L-leucyl-L-leucine methyl ester, also activates the NALP3 inflammasome. These findings suggest that the NALP3 inflammasome senses lysosomal damage as an endogenous danger signal, leading to the activation of inflammatory cytokines and recruitment of immune cells. The study highlights the role of lysosomal function in crystal-induced inflammation and provides insights into the mechanisms underlying silica crystal-induced lung inflammation and fibrosis.