Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis.

The clinical utilization of doxorubicin (Dox) in various malignancies is restrained by its major adverse effect: irreversible cardiomyopathy. Extensive studies have been done to explore the prevention of Dox cardiomyopathy. Currently, ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy. Sorting Nexin 3 (SNX3), the retromer-associated cargo binding protein with important physiological functions, was identified as a potent therapeutic target for cardiac hypertrophy in our previous study. However, few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy. In this study, a decreased level of SNX3 in Dox-induced cardiomyopathy was observed. Cardiac-specific Snx3 knockout (Snx3-cKO) significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly. SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro, and cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC) via direct interaction, disrupting iron homeostasis, increasing the accumulation of iron, triggering ferroptosis, and eventually exacerbating Dox-induced cardiomyopathy. Overall, these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRC-dependent ferroptosis.

Long non-coding RNA MALAT1 regulates cell proliferation, invasion and apoptosis by modulating the Wnt signaling pathway in squamous cell carcinoma.

OBJECTIVE: To explore the mechanisms by which long non-coding RNA, (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates cell proliferation, invasion and apoptosis through signaling axes in cutaneous squamous cell carcinoma (CSCC) cells. METHODS: A total of 60 CSCC samples and 15 normal skin tissue samples were collected. qRT-PCR was used to determine MALAT1 expression. After knockdown of MALAT1 expression in A431 cells, Transwell assay was performed to detect cell migration and invasion, CCK8 assay was used to detect cell proliferation, and Western blotting was used to detect EMT-related protein expression. RESULTS: Compared with the normal group, the MALAT1 positive expression rate was significantly higher in the low, moderate, and high differentiation groups (P < 0.05). The expression of MALATl in A431 cells in the siMALATl-1 and siMALATl-2 groups was lower than that in siNC group (P < 0.05). A431 cell proliferation, invasion and apoptosis at 24 h, 48 h and 72 h in the siMALATl-1 and siMALATl-2 groups were all lower and the apoptosis rate of A431 cells were all higher than that of the siNC group (P < 0.05). E-cadherin expression was higher while the expression of ß-catenin, vimentin, and Bcl-2 was lower in the siMALATl-1 and siMALATl-2 groups than those of the siNC group (P < 0.05). CONCLUSION: Down-regulation of lncRNA MALAT1 expression may promote apoptosis of CSCC cells and inhibit cell migration, invasion and proliferation by regulating the Wnt signaling pathway.