A new study released on 18th July 2025 in “Frontiers in Endocrinology” has revealed that the gene SDR42E1 is key to the absorption and metabolism of vitamin D – and when inactivated in colorectal cancer cells, can drastically reduce their survival. Not only that, but inactivating this gene also disrupted thousands of other genes linked to cancer. This breakthrough points to exciting possibilities for precision cancer therapies.
What is SDR42E1?
SDR42E1 belongs to the short‑chain dehydrogenase/reductase (SDR) enzyme family. It is encoded on chromosome 16, and a known nonsense variant (rs11542462) creates a truncated, nonfunctional version of SDR42E1. Previous genome‑wide association studies linked this variant with vitamin D deficiency, as individuals carrying it tend to have elevated levels of 7‑ and 8‑dehydrocholesterol (precursors to vitamin D) and correspondingly lower calcitriol.
CRISPR Experiment in Colorectal Cancer Cells
Researchers used the human colorectal carcinoma cell line HCT116, which naturally expresses SDR42E1 at high levels – suggesting that the cancer cells rely on the gene for survival. Using CRISPR/Cas9, they edited the SDR42E1 gene to introduce the inactivating mutation (creating a homozygous knock‑in form) in HCT116 cells.
Effect on Cancer Cell Viability
The results were staggering: cell viability dropped by approximately 53% when SDR42E1 was rendered inactive. This dramatic effect goes to show just how important SDR42E1 is for the survival of these cancer cells. Not only that, but re‑expressing SDR42E1 reversed the decline in survival, confirming the gene’s functional significance.
Transcriptomic and Proteomic Rewiring
Upon inactivation, a massive 4,663 downstream genes altered their expression, indicating SDR42E1 functions as a central molecular switch. Specifically:
- Genes involved in cancer-related signalling – including WNT pathway members and cell‑cycle regulators – were among the most significantly disturbed.
- Genes and transporters involved in sterol absorption and metabolism, such as LRP1B, ABCC2, LDLR, SLC7A5, and DHCR24, showed dramatic expression changes – aligning with SDR42E1’s key role in calcitriol synthesis.
- Proteomic profiling mirrored these findings: proteins essential for proliferation and metabolism – such as ALDOA, FASN, ACSL5, and ABCC2 – showed altered levels in SDR42E1‑deficient cells.
Two Different Therapeutic Strategies
Researchers propose a dual‑direction therapeutic model:
- Inhibition of SDR42E1 could specifically target and kill cancer cells that depend heavily on vitamin D metabolism – effectively “starving” them of calcitriol while leaving normal cells largely unharmed.
- Enhancement or local overexpression of SDR42E1 could boost local calcitriol production, which may have protective effects in conditions linked to vitamin D deficiency (e.g., bone disease, immune disorders, metabolic impairments and possibly cancer prevention).
However, the researchers stress that long‑term impacts remain uncertain, as dialling up SDR42E1 systemically could affect lipid metabolism or immune regulation in complex ways, so careful validation is required.
Scope and Limitations
Despite the compelling results, the study has limitations:
- It was conducted in vitro using HCT116 cancer cells, which may not replicate vitamin D metabolism’s dynamics in healthy human intestinal tissue.
- There is risk of off‑target effects using CRISPR, which could confound results.
- Functional assays such as apoptosis, migration, and vitamin D rescue experiments were not included.
- The health consequences of altering SDR42E1 in mammals, especially over longer timeframes, remain unknown.
Implications For Future Cancer Treatment
By showing that inactivating just one gene can simultaneously disrupt tumour cell viability and rewire thousands of downstream molecular pathways, the findings from this study offer a roadmap for precision oncology. The discovery could be a dream come true – a gene‑based therapeutic switch that may selectively kill cancer cells with minimal harm to healthy tissue.
At the same time, the possibility of enhancing SDR42E1 activity opens doors to new treatments for diseases influenced by vitamin D imbalance – though safety and systemic metabolic effects will require rigorous future study.
However, translating the insights from this study into clinical practice will demand extensive in vivo validation, safety assessment, and mechanism-focused research. But if successful, manipulating SDR42E1 could become a powerful tool to starve tumours of calcitriol or conversely boost local vitamin D activity in deficiency‑linked diseases – perhaps heralding a new era where one gene holds the potential to shift the balance between disease and health. What a very exciting prospect this is.
