Tetrahydromagnolol targets TRIM38 to mediate PANoptosis in cancer cells and has the potential for synergistic cancer therapy.

BACKGROUND: Tetrahydromagnolol (THM) is a compound isolated from Magnolia officinalis with unique chemical structure and composition. However, its anticancer effect of THM and the underlying molecular mechanisms remain unclear. METHOD: Firstly, the anticancer effects of THM on different cancer cell lines in vitro were investigated. Subsequently, the antitumor activity of THM was further evaluated in vivo and in vitro using colorectal and lung cancer models. This assessment involved the effects of THM on cell viability, apoptosis, proliferation, cell cycle progression, and tumor growth inhibition. In addition, the anticancer molecular mechanisms of THM were determined by RNA sequencing, western blot, immunohistochemistry, immunofluorescence, CETSA, and SPR. Meanwhile, the effects of THM on organelles were evaluated by measuring endoplasmic reticulum stress, mitochondrial membrane potential damage, reactive oxygen species (ROS), and calcium ion concentration. Finally, the efficacy of THM in combination with conventional anticancer drugs for colorectal cancer treatment was evaluated in vivo. RESULTS: The results showed that THM had a significant anticancer activity in colorectal cancer and lung cancer both in vitro and in vivo. THM significantly inhibited cell proliferation and induced PANoptosis-like cell death through GSDME mediated pyroptosis, CASP3 mediated apoptosis, and MLKL mediated necroptosis. In addition, the anticancer potential of THM was also related to elevation of endoplasmic reticulum stress, mitochondrial membrane potential destruction, and increase of ROS and intracellular calcium concentration. Mechanically, we found that THM could directly bind to triplet motif-containing 38 (TRIM38) and induced its upregulation at mRNA and protein levels. Importantly, knockdown of TRIM38 remarkably rescued the anticancer effects of THM and PANoptosis induced by THM treatment, suggesting that TRIM38 played a key role in mediating the antitumor activity of THM. In addition, THM showed significant synergistic therapeutic effects when used in combination with conventional anticancer strategies (Cetuximab, FOLFOX, and FOLFIRI regimens) for colorectal cancer treatment. CONCLUSION: Our data suggest that THM exerts its anticancer potential by inducing TRIM38-dependent PANoptosis and it also has synergistic antitumor effects in combination with conventional anticancer strategies. THM will be a promising candidate drug used alone or in combination with other anticancer regimens for cancer treatment.