salinomycin (HSB-1216)

Mechanistic studies using cycloheximide chase assays, Wnt pathway modulators (LiCl, SKL2001, and Salinomycin), and protein interaction analyses demonstrated that KCNJ12 stabilizes β-catenin through the physical interaction with lipoprotein receptor-associated protein 6 (LRP6), disrupting AXIN/APC/GSK-3β complex assembly and subsequent proteasomal degradation...Our findings establish KCNJ12 as a novel Wnt/β-catenin regulator and propose dual therapeutic strategies against HCC-mediated chemoresistance: pharmacological suppression of KCNJ12 channel activity and targeted disruption of KCNJ12-LRP6 protein interactions. This mechanistic framework advances our understanding of stemness regulation in HCC and provides feasible targets for developing next-generation anti-HCC therapies.

In conclusion, the combination of Sal and D4476 suppressed the growth of HCT116 CRC cells by inducing ferroptosis and inhibiting autophagic flux. This research could lead to a novel method of using Sal in the clinic as a new antitumor drug, particularly when combined with other therapies that target the p62-NRF2 axis, such as D4476.

Sal promoted an increase of Annexin-V positive cells in Huh-28 and RBE cells in a dose-dependent manner, which was efficiently inhibited by VX-765 (Caspase-1 inhibitor), while Sal-induced increase of ROS levels was partially inhibited by exposure to N-acetyl-L-cysteine (ROS scavenger). The activation of Sal on the ROS/NF-κB/NLRP3 pathway was also identified in CCA cells and tumor tissues. Collectively, these results suggested that Sal activated the ROS/NF-κB/NLRP3 pathway to promote pyroptosis-induced cell death in CCA and suggest it may be a promising treatment strategy for anti-CCA.

Notably, compounds such as berberine and piperine were found to reverse drug resistance by downregulating efflux transporters, while quercetin and salinomycin selectively induced apoptosis in CSCs. Overall, natural compounds show promising potential for targeting CSCs in therapy. However, challenges related to bioavailability and metabolic stability must be addressed through advanced drug delivery systems and combination therapy.

These changes indicate disruption of the Wnt/β-catenin signaling pathway, enhancing TRAIL-mediated apoptosis in TNBC cells. These findings demonstrate promising in vitro therapeutic efficacy of CS-SAL-LPNPs, warranting further preclinical in vivo studies for comprehensive validation.

Moreover, after screening for a suitable ratio of salinomycin and chloroquine (1:2.5), compared to salinomycin group, salinomycin+chloroquine group exhibited decreased tumor spheroid number and volume of MCF-7-TS cells; reduced B-cell lymphoma-2 (Bcl-2), LC3, LC3II/LC3I, and Beclin-1 expression; and enhanced G0/G1 phase arrest and Bcl-2-associated X protein expression in MCF-7 and MCF-7-TS cells. Chloroquine enhanced the anticancer efficacy of salinomycin by suppressing salinomycin-induced autophagy, providing a solid theoretical basis for its clinical application in BC.

It may provide more and novel solutions and treatment perspectives for 5-FU or other drug-resistant chemotherapy strategies for patients with CRC. SAL inhibits CRC, whose effect is achieved by reducing GPX4 and SLC7A11 protein levels to mediate ferroptosis activation in collaboration with 5-FU.

Importantly, our findings extend beyond maduramicin, as other IPAs including monensin and salinomycin similarly targeted TFEB, triggering hepatocyte ferroptosis...These findings establish TFEB-mediated NCOA4-dependent ferritinophagy and ferroptosis as central mechanisms in IPAs-induced hepatotoxicity, thereby identifying TFEB as a promising therapeutic target for mitigating IPAs-induced liver damage. This study provides critical insights into the molecular mechanisms of IPAs-induced liver injury and offers a novel strategy for therapeutic intervention.

Salinomycin treatment mitigates resistance to sorafenib-induced ferroptosis by inhibiting SREBP1. The combination of salinomycin and sorafenib synergistically enhances ferroptosis and suppresses ccRCC growth.

Pretreatment with N-acetylcysteine (NAC) reversed this effect. SAL enhances OXA-induced antitumor effects in CRC both in vitro and in vivo by ROS-mediated mitochondrial apoptosis and activation of the MAPK pathway. These results may provide a rationale for combining SAL with OXA for CRC treatment.

We used four stemness inhibitors-salinomycin, SB-431542, JIB-04, and napabucasin-each targeting different pathways (Wnt/β-catenin, TGF-β, histone demethylation, and STAT3, respectively), to evaluate their effects on CMS4 CRC cell lines (HCT116 and SW620) and human peripheral blood-derived macrophages in an indirect co-culture model. Our study highlights the dual potential of stemness inhibitors to target both cancer cells and the immune microenvironment. These findings offer promising strategies for enhancing favorable immunomodulation in mesenchymal-like colorectal tumors.

Salinomycin plays the role of "eliminating pathogenic qi," targeting cancer stem cells; FMT plays the role of "strengthening vital qi," reversing the intestinal microbiota disorder and enhancing anti-cancer immunity. They have a synergistic effect on the development of CRC.