Gillespie, Z. | Search bioRxiv

bioRxiv2026

A Broad-Spectrum Chemokine Inhibitor Prevents Preterm Labor in Mice by Supressing Inflammation Induced by Intra-Amniotic Injection of Interleukin-1 alpha

Preterm birth (PTB) is a leading cause of perinatal and infant mortality worldwide. PTB can be induced by systemic maternal or intra-uterine infection or by sterile intra-amniotic inflammation driven by alarmins such as interleukin-1 (IL-1). We reported earlier that a Broad-Spectrum Chemokine Inhibitor (BSCI) prevented PTB in murine and non-human primate models of infection-mediated preterm labor. Here, we investigated whether BSCI can prevent PTB in pregnant C57BL/6 mice following ultrasound-guided intra-amniotic injection of IL-1 (400 ng per sac) on gestational day (GD)16.5. Half the mice received BSCI (10 mg/kg, intravenous daily) beginning GD15.5 and through to term. The impact of IL-1 alone or IL-1 plus BSCI was assessed on (i) injection-to-delivery interval, fetal survival, placental and neonatal weight; (ii) cytokine and chemokine levels in maternal plasma and amniotic fluid and inflammatory gene expression in maternal and fetal tissues (Real-Time RT-qPCR); (iii) global transcriptomic profiling of myometrial tissues at 2 and 24 hrs (RNA sequencing) together with examination of myometrial chromatin accessibility (Assay for transposase accessible chromatin sequencing) at 24 hrs; (iv) uterine leukocyte infiltration (immunofluorescence). Pretreatment with BSCI i) prevented IL-1-induced PTB; (ii) significantly attenuated cytokine and chemokine signals in maternal plasma, myometrium, decidua, and placenta, and amniotic fluid; (iii) suppressed myometrial contraction-associated genes, including Nfkb1, Ptgs2, Akr1c18, and Gja1; (iv) prevented global IL-1-induced changes in myometrial gene expression and chromatin accessibility (v) reduced uterine macrophage (F4/80+) counts and prevented the increase in pro-inflammatory M1-like macrophages observed with IL-1-treatment. BSCI-treated dams that delivered at term had live pups with normal placental and fetal weight. Taken together, BSCI reduced the incidence of IL-1-mediated PTB and maintained uterine quiescence by suppressing uterine inflammation and genome-wide changes in labor gene expression and chromatin accessibility. BSCI represents a promising therapeutic approach for PTB prevention in high-risk pregnant women.

physiology↗

bioRxiv2025

Heterochromatin fidelity is a therapeutic vulnerability in lymphoma and other human cancers

Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTSO_LIPhenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma C_LIO_LIJIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin C_LIO_LIKDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers C_LIO_LIHigh-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors C_LI

genomics↗