CX-5461 is a potent immunosuppressant which inhibits T cell-mediated alloimmunity via p53-DUSP5

Editorial: Drugging p53 for non-cancer diseases

“…However, CX-5461 did not induce a systemic anti-inflammatory transcriptional program in macrophages, although some pro-inflammatory genes, such as interleukin-1β and gp91phox NADPH oxidase, were downregulated by CX-5461. Consistent with their previous observations ( Dai et al, 2018 ; Xu et al, 2021 ; Pan et al, 2022 ), this study confirmed a central role of p53 in orchestrating the molecular responses in macrophages to CX-5461 treatment. The authors suggested that limiting cell proliferation was the predominant mechanism of the inhibitory effects of CX-5461 on macrophage-mediated inflammation, and these data might provide a molecular framework for understanding the mechanisms underlying the anti-inflammatory properties of CX-5461.…”

“…In this Research Topic, Wang et al reported their work on identifying the molecular mechanisms underlying the anti-inflammatory effects of CX-5461, a novel selective RNA polymerase I inhibitor which induces nucleolar stress and p53 activation (phosphorylation), in macrophages. This study extended their previous findings that CX-5461, in addition to its anti-tumor activity, exhibited significant anti-inflammatory and immunosuppressive effects ( Dai et al, 2018 ; Xu et al, 2021 ; Pan et al, 2022 ). The authors utilized contemporary systemic biology techniques (genome-wide RNA sequencing).…”

A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage

“…Although the available data regarding the role of p53 in modulating inflammatory reactions appear to be controversial, a mass of evidence suggests that p53 has anti-inflammatory activities in certain pathological contexts (see Cui et al, 2021 ). In a recent study we have shown that CX-5461 can inhibit T cell-mediated immunity functions via p53-DUSP5 (dual-specificity phosphatase 5) axis and subsequent antagonism of the Erk1/2 mitogen-activated protein kinase activity, thereby preventing the occurrence of acute transplant rejection ( Pan et al, 2022 ). These results suggest that CX-5461 has independent modulatory activities on inflammatory/immune signalings in immune cells apart from regulation of the cell cycle.…”

“…According to the observations from our previous studies (Ye et al, 2017;Dai et al, 2018;Pang et al, 2021;Xu et al, 2021;Pan et al, 2022), activation of the p53 pathway following Pol I inhibition (rather than reduced productions of rRNAs and ribosomes) appears to have a predominant role in mediating CX-5461 effects. This phenomenon has also been recognized in cancer cells (Ferreira et al, 2020).…”

Novel RNA polymerase I inhibitor CX‐5461 suppresses imiquimod‐induced experimental psoriasis

“…Interestingly, in these studies, we observed that CX‐5461 exhibited inhibitory effects on macrophage‐mediated vascular inflammation 15,16 . More recently, we identified that CX‐5461 was a novel immunosuppressant, which blocked acute transplant rejection by repressing T‐cell‐mediated alloimmunity via induction of DUSP5 (dual‐specificity phosphatase 5) expression 18 …”