Can the "Third Gasotransmitter" Unlock New Cancer Therapies?
"Unveiling the potential of 3-MST and hydrogen sulfide pathways in cancer research and treatment, addressing a critical gap in understanding how these biological systems affect cancer cell behavior."
Hydrogen sulfide (H2S) has moved from being considered a toxic gas to being recognized as a crucial biological messenger in our bodies. Alongside nitric oxide (NO) and carbon monoxide (CO), H2S is now known to regulate various cellular functions. Understanding how H2S works and how it’s produced in our cells is critical for developing new treatments for various diseases.
While scientists have primarily focused on two enzymes, cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS), as the main sources of H2S, a third enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), is gaining attention. Researchers are investigating its potential role in cancer, due to its unique characteristics, such as its location within cells and its ability to produce polysulfides, which can modify proteins.
This article explores the potential of 3-MST and H2S in cancer, highlighting how cancer cells use these molecules to support their growth and survival. It also identifies gaps in our current knowledge and suggests directions for future research.
Cancer Data and 3-MST
The CDC says cancer data are used to understand cancer rates and trends, support research, measure progress in cancer control and prevention, focus action on eliminating disparities, and improve outcomes for all. Research identified 3-mercaptopyruvate sulfurtransferase (3-MST) as an enzyme capable of producing hydrogen sulfide. Reviews report that 3-MST plays an important role in cancer development and progression, making regulation of its expression a potential therapeutic strategy. A March 2026 preprint further reported that 3-MST was markedly upregulated in colorectal cancer stem cells and supported this therapy-resistant population metabolically.
Targeting the 3-MST/H2S Axis
Studies using newly discovered pharmacological inhibitors and 3-MST silencing approaches suggest that the 3-MST/hydrogen sulfide system helps maintain cancer-cell proliferation. The pathway may also regulate bioenergetic and cell-signaling functions. A 2023 review describes 3-MST as directly or indirectly regulating pathways involved in cancer progression. A technical guide frames the 3-mercaptopyruvate/3-MST axis as requiring careful handling of an unstable substrate, validation of enzymatic activity, and pathway-targeting methods.
From H2S Biology to Cancer Therapy
The research trajectory has focused on how 3-MST facilitates the endogenous generation of hydrogen sulfide and polysulfides. Reviews published through DOAJ and ResearchGate describe growing attention to 3-MST's potential role in tumorigenesis and tumor development. They also highlight studies examining how 3-MST inhibition affects tumor development and could support tumor therapy. This progression has shifted the enzyme from a biochemical subject toward a possible therapeutic target.
Why 3-MST Matters in Cancer Research
3-MST has been recognized as a mammalian protein for decades. It exists as a 33 kDa enzyme that depends on zinc. The active form consists of a monomer-dimer equilibrium, with the 3-MST monomer being the active component. Two specific cysteines, Cys154 and Cys263, are key in forming intermolecular disulfide bonds, which directly impacts how well the enzyme functions.
- Antioxidant and Detoxification: Early research highlighted 3-MST's role in protecting cells from damage by acting as an antioxidant and helping in detoxification processes.
- tRNA Thiolation: 3-MST is also critical in modifying transfer RNAs (tRNAs), essential molecules involved in protein synthesis. In this context, 3-MST is referred to as TUM1 (tRNA thiouridin modification protein 1).
- Production of H2S and Polysulfides: More recently, 3-MST has been recognized for its ability to produce hydrogen sulfide (H2S) and polysulfides. These molecules have significant biological activity, influencing various cellular processes.
Triple-Negative Breast Cancer Findings
A 2026 Frontiers study examined 3-MST-derived hydrogen sulfide in triple-negative breast cancer chemoresistance. In MDA-MB-231 cells, HMPSNE enhanced doxorubicin's cytotoxic, anticlonogenic, and antimigratory effects. The finding suggests that targeting this pathway may improve the activity of an existing chemotherapy in a laboratory model. It does not by itself establish clinical benefit in patients.
Evidence and Inhibitor Limits
Evidence for hydrogen sulfide-pathway targeting is not limited to 3-MST: one review reports that CBS overexpression contributes significantly to breast-cancer pathogenesis and that CBS silencing produced antitumor effects in vitro and in vivo. However, pharmacological experiments can be confounded by nonspecific effects on cell viability. One study states that HMPSNE was then the only specific, cell-permeable 3-MST inhibitor available, limiting confirmation with other inhibitor classes. Another review cautions that earlier work often relied on correlations and inferences because suitable inhibitors were unavailable and 3-MST silencing was rarely used.
CBS and 3-MST Comparisons
In murine breast cancer cells, pharmacological inhibition of either CBS or 3-MST inhibited hydrogen sulfide production, suppressed cellular bioenergetics, and attenuated proliferation. In murine colon cancer cells, pharmacological 3-MST inhibition concentration-dependently suppressed hydrogen sulfide production. At 100 and 300 µM, it also attenuated CT26-cell proliferation and migration. Together, these studies support overlapping effects of CBS and 3-MST inhibition while showing that the reported colon-cancer effects were concentration-specific.
Future Directions: Unlocking 3-MST's Full Potential
While it's clear that the 3-MST/H2S system plays a role in cancer, many questions remain. Future research needs to clarify how this system interacts with other elements in the cellular environment and how it affects cancer cell energetics, signaling, and survival. With the development of specific 3-MST inhibitors and advanced research tools, we are now better equipped to explore these questions and potentially develop new cancer therapies.
Why the Pathway Matters
A review of hydrogen sulfide's molecular functions reports that H2S can promote tumor growth, cellular and mitochondrial bioenergetics, migration, invasion, angiogenesis, tumor blood flow, metastasis, epithelial-mesenchymal transition, DNA repair, protein sulfhydration, and chemotherapy resistance. The same review states that increased expression of H2S-synthesizing enzymes correlates with worse prognosis and higher tumor stage in some malignancies. These observations make the pathway biologically important, while also indicating that its effects can span multiple cancer processes. They support continued investigation rather than proving that one universal H2S-targeting treatment will work across cancers.
Clinical Questions in Colorectal Cancer
A study published on August 16, 2026, investigated 3-MST's contribution to colorectal-cancer-associated angiogenesis, blood-vessel function, tumor growth, and tumor-cell proliferation. Its authors noted that the role of 3-MST in the pathophysiology of colorectal-cancer-associated angiogenesis remained to be explored. The work therefore addresses processes that could affect tumor behavior and the tumor-associated blood supply. Its stated research focus also underscores that the real-world clinical significance of 3-MST remains an active question.