Vision loss in this corneal infection arises primarily from the host inflammatory response, not from the bacteria themselves, and rising antimicrobial resistance narrows the benefit that antibiotics alone can deliver. To map that machinery, the researchers injected LPS into the corneal stroma of mice and compared three groups: untreated controls, LPS-treated animals, and LPS-treated animals given AZD6738, with three mice per group. Corneas harvested at 48 hours underwent RNA sequencing.

Differential expression analysis with DESeq2 revealed the scale of the inflammatory response: LPS upregulated 1,622 genes and downregulated 140, each with an adjusted p-value below 0.05 and a log₂ fold change greater than 1 in magnitude. Those genes were enriched across 80 immune-related pathways identified by KEGG analysis. The drug’s effect was then quantified by regressing the treatment-induced expression changes on the LPS-induced changes.

The analysis indicated that AZD6738 reversed approximately 57% of the LPS-induced transcriptional alterations, and 51.2% of the genes upregulated by LPS were significantly reversed. In other words, the inhibitor did not merely blunt a handful of inflammatory markers; it pulled a substantial fraction of the entire disease-associated transcriptome back toward its baseline state. The key to understanding how lay in transcription factor regulon analysis.

Using TRRUST v2 gene set enrichment, the team defined an inflammatory transcription factor program spanning NF-κB, IRF, STAT, AP-1 and myeloid lineage families. Strikingly, when the same regulon analysis was applied to a human bacterial keratitis transcriptome dataset (GSE241715, comprising 4 cases and 7 controls), the normalized enrichment scores of the two species were strongly rank-correlated — a Spearman ρ of 0.62 across 214 regulons, with a p-value of 3.4 × 10⁻²⁴. Four regulators were significant in both species: NFKB1, RELA, SPI1 and STAT1.

AZD6738 treatment shifted the activity of these conserved regulons to negative enrichment values, with normalized enrichment scores ranging from −2.81 to −2.56, indicating coordinated suppression of the inflammatory program rather than scattered effects on individual genes. Mechanistic experiments in RAW264.7 macrophage cells supported that interpretation: when the NF-κB subunit p65 was overexpressed and the cells stimulated with LPS, AZD6738 reduced NF-κB-driven transcription and phosphorylation of p65 at serine 536. Tolerability was assessed separately in HCE-T human corneal epithelial cells, addressing the practical question of whether the compound could be compatible with ocular tissue.

The authors conclude that AZD6738 reverses a substantial portion of the LPS-induced corneal inflammatory transcriptome and suppresses an inflammatory transcription factor program whose regulons are conserved in human bacterial keratitis. On that basis, they argue the data support ATR inhibition as an adjunct to antimicrobial therapy in bacterial keratitis — a strategy that would target the host response while antibiotics continue to attack the infection itself. Several caveats frame the result.

The mouse experiment involved only three animals per group, the human comparison relied on a small transcriptome dataset of four cases and seven controls, and the mechanistic work was performed in cell lines rather than living corneas. What the work does establish is a molecular bridge: an ATR inhibitor converges on an NF-κB-centered transcriptional network that appears to operate in both the mouse model and human disease, offering a defined mechanistic foundation for further evaluation of host-directed therapy in corneal infection.

Subject of Research: ATR inhibition as a host-directed approach to inflammatory gene programs in bacterial keratitis

Article Title: AZD6738 reverses the LPS-induced corneal inflammatory transcriptional program through a conserved transcription factor network converging on NF-κB

Article References: Ye, Q., Chen, K., Huang, L., Chen, Y., Chen, D., Zhou, B., & Zhu, Y. (2026). AZD6738 reverses the LPS-induced corneal inflammatory transcriptional program through a conserved transcription factor network converging on NF-κB. Frontiers in Medicine, 13, Article 2005671. https://doi.org/10.3389/fmed.2026.2005671

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.2005671

Keywords: AZD6738, ATR inhibitor, bacterial keratitis, NF-κB, transcription factor regulons, LPS, corneal inflammation, RNA sequencing, host-directed therapy, ophthalmology, reverses, LPS-induced