Dihydroartemisinin Drives SP1 Degradation to Slow Melanoma Growth

A new study published in Cellular & Molecular Biology Letters reports that the compound acts as a molecular glue, promoting the ubiquitination and proteasomal degradation of SP1, a transcription factor that melanoma cells rely on to sustain proliferation and migration.

Melanoma remains one of the deadliest tumor types, with low survival rates driven by high recurrence, rapid metastatic spread and drug resistance. Although earlier work showed that dihydroartemisinin suppresses melanoma cell proliferation and migration, the mechanism behind those effects had remained unclear. The new research, led by Long Cao, Jiaqi Wu and colleagues with senior author Guoqiang Xu, was published on 29 September 2026 as an open-access article.

To uncover the mechanism, the team performed RNA sequencing on melanoma cells treated with the drug. The analysis revealed that dihydroartemisinin upregulates 790 genes and downregulates 2,342 genes in melanoma cells. Among the most significantly downregulated genes was cadherin-3, or CDH3, a gene the study found to be functionally important for tumor growth.

The experiments showed that CDH3 expression augments melanoma cell proliferation, while knocking the gene down attenuates it. That finding positioned CDH3 as a pro-tumor factor whose loss would be expected to slow melanoma growth, prompting the researchers to trace how the drug suppresses it.

The answer lay upstream of CDH3. SP1 is the transcription factor that controls CDH3 expression, and the study found that dihydroartemisinin facilitates the ubiquitination and proteasomal degradation of SP1. The drug does this by enhancing the interaction between SP1 and KEAP1, the substrate receptor of an E3 ubiquitin ligase, which marks SP1 for destruction by the proteasome.

With SP1 degraded, the downstream signaling cascade collapses. The researchers report that dihydroartemisinin inhibits the CDH3/PI3K/AKT/GSK3β/β-catenin signaling pathway, a chain of molecular events closely tied to cell survival, growth and migration in many cancers, including melanoma.

The team also tested the mechanism in animals. In a xenograft mouse model, restoring SP1 expression rescued melanoma cells from the inhibitory effect of dihydroartemisinin, providing evidence that SP1 degradation is central to the drug’s antimelanoma activity rather than a side observation.

Collectively, the authors describe their work as elucidating an unrecognized mechanism by which dihydroartemisinin suppresses melanoma cell proliferation and migration by acting as a molecular glue that promotes SP1 ubiquitination and proteasomal degradation. They suggest the discovery sheds new insight into how the compound works and its potential in translational research.

The findings come with caveats typical of early mechanistic cancer studies. The core results were obtained in cell lines and a xenograft mouse model, and the article was shared early as a peer-reviewed, accepted version that is subject to further edits before the final Version of Record. Clinical efficacy in melanoma patients has not been established, and the authors frame the work as a foundation for future translational research rather than a validated therapy.

By identifying SP1 degradation through the KEAP1 pathway as a specific antimelanoma mechanism, the research offers a concrete molecular target for future studies aimed at improving melanoma treatment.

Subject of Research: A molecular mechanism by which dihydroartemisinin inhibits melanoma cell proliferation and migration through SP1 ubiquitination and degradation

Article Title: Targeting SP1 for ubiquitination and degradation: a novel antimelanoma mechanism of dihydroartemisinin

Article References: Cao, L., Wu, J., Doyle, L., Zhao, Y., Li, J., Hu, H., Shang, X., Zhou, Z., Wu, L., Wang, Y., Liu, Y., Mao, L., Hu, Z., Zhou, L., Ma, J., Zheng, W., & Xu, G. (2026). Targeting SP1 for ubiquitination and degradation: a novel antimelanoma mechanism of dihydroartemisinin. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01027-2

Image Credits: AI Generated

DOI: 10.1186/s11658-026-01027-2

Keywords: dihydroartemisinin, melanoma, SP1, KEAP1, ubiquitination, CDH3, PI3K/AKT signaling, molecular glue, proteasomal degradation, xenograft model, RNA sequencing, artemisinin derivative