Late occurrence of breast cancer brain metastases in patients pretreated with systemic therapies is often associated with therapy resistant brain metastatic lesions. Prior studies targeting previously identified mediators of resistance have yielded limited success, especially in the case of brain metastatic breast cancer (BMBC). Trefoil Factor 1 (TFF1) has been associated with therapy resistance in Estrogen Receptor (ER) positive breast cancer. However, its role in therapy resistance of triple negative and HER2+ breast cancer remains elusive. Herein, we assessed the involvement of TFF1 in therapy resistant triple negative and HER2+ BMBC. We developed Paclitaxel resistant triple negative and Lapatinib resistant HER2+ BMBC cells by dose escalation method. Drug efflux transporter ABCB1 in Paclitaxel resistant cells and ABCG2 in Lapatinib resistant cells were significantly upregulated. Additionally, cancer stem cell marker, CD24, showed significant upregulation in both resistant cell lines while anti-apoptotic protein BCL2 was upregulated only in Lapatinib resistant cells. Importantly, TFF1 was significantly upregulated in both Paclitaxel and Lapatinib resistant BMBC cells. Moreover, siRNA mediated TFF1 silencing partially alleviated resistance in both Paclitaxel and Lapatinib resistant BMBC cells. Our study shows that TFF1 is potentially associated with resistance to Paclitaxel and Lapatinib in both triple negative and HER2+ BMBC.

The 3rd Codon Usage Conference: Function, Mechanism and Evolution was held May 31 to June 3, 2026, at the Bibliothèque et Archives nationales du Québec in Montreal, Canada. Here, I provide summaries of the talks that were given at the meeting, and I discuss major advancements in the field.

Plant cells are turgid and exert pressure against a stiff extracellular matrix, the plant cell wall, which resists turgor pressure and prevents cell bursting due to osmotic pressure. During growth, the cell wall yields under turgor pressure and deforms to guide the expansion of the cytoplasm. Together, these suggest that the mechanical properties of the cell wall are tightly regulated during development and that a tight coordination between turgor pressure and cell wall plasticity is required. In this review we explore the anisotropic mechanical properties of the cell wall and the mechanisms involved in its regulation. We discuss some of the theories supporting passive regulation of the cell wall such as the multinet theory and the scaffolding theory. We then discuss the role of CrRLK1Ls such as FERONIA and mechanosensing ion channels like MSL8 in the perception of mechanical stress and the role of Ca2+ as a central second messenger of mechanical stress response. Finally, we highlight some of the transcriptional responses induced by mechanosensing via small signal peptides such as SCOOP and Pep1 and cell wall remodelling enzymes such as TCH4.

Ceramide-1-phosphate (C1P), once considered a minor metabolic intermediate, is now recognized as a relevant regulator of cell survival, inflammation, migration, oxidative stress, glucose uptake, and adipogenesis. These diverse functions are mediated by direct interactions between C1P and specific protein targets, including enzymes, lipid transfer proteins, and signaling effectors (typically proteins). While C1P was demonstrated to regulate a variety of signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase kinase (MEK)/extracellularly regulated kinases (ERK) 1-2, or sphingomyelin synthase (SMS)/protein kinase-C-alpha (PKCα), this review namely focuses on the eight major proteins that directly interact with C1P: acidic sphingomyelinase (ASMase), serine palmitoyl transferase (SPT), Ca2+-dependent cytosolic phospholipase A2-alpha (cPLA2α), Gi protein-coupled receptors, C1P transfer protein (CPTP), sphingomyelinase phosphodiesterase like 3b (SMPDL3b), annexin A2-p11 (S100A10), and Kelch-like ECH-associated protein 1 (KEAP1). Understanding C1P-protein interactions provides a conceptual framework for targeting sphingolipid signaling in inflammation, cancer and metabolic diseases. Here, we summarize current evidence for C1P binding or functional modulation of these proteins, and highlight the implications of these interactions in inflammation, oxidative stress control, and disease pathogenesis.

Heat shock proteins (HSPs) are essential molecular chaperones that maintain protein homeostasis and protect cells under stress. Their extracellular functions have emerged as pivotal in cancer biology. Extracellularly released HSPs are selectively packaged through stress-responsive pathways and exhibit context-dependent effects within the tumor microenvironment. They can modulate immune cell functions, act as danger signals, and promote immune activation or suppression. Clinically, extracellular vesicle (EV)-HSPs demonstrate potential as diagnostic and prognostic biomarkers. It has been shown that they can outperform their soluble counterparts due to enhanced stability and tumor specificity. This mini-review aims to highlight findings related to the roles of EV-HSPs and their potential applications.

High-density lipoprotein (HDL) functionality has emerged as a key determinant of residual cardiovascular risk despite advances in low-density lipoprotein-cholesterol lowering therapies. Small HDL particles, generated through ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux, are particularly effective in promoting cholesterol removal from macrophage foam cells and are associated with reduced atherosclerotic risk. Probucol, a lipid-lowering drug, inhibits ABCA1-dependent HDL biogenesis, whereas its major metabolite, 3,3',5,5'-tetra-tert-butyldiphenoquinone (DQ), preserves the generation of small HDL particles. However, the molecular basis for these distinct effects has remained unclear. To investigate the structural mechanisms underlying ABCA1-mediated lipid export, we performed molecular docking analyses using the human ABCA1 structure (Protein Data Bank, PDB: 5XJY) and the Genetic Optimization for Ligand Docking in silico docking platform. Cholesterol and 1-palmitoyl-2-oleoyl-phosphatidylcholine docking poses were successfully identified in DQ-bound ABCA1. In contrast, no ligand-binding poses were detected in probucol-bound ABCA1. These findings suggest that DQ preserves the lipid-recognition and transport properties of ABCA1, whereas probucol disrupts ligand accommodation within the transporter. This study provides the first atomic-level insight into the interactions among ABCA1, cholesterol, probucol, and DQ, offering a structural explanation for their distinct effects on HDL biogenesis and identifying a potential framework for developing novel HDL-targeted therapeutics.

Hypertrophic scars (HS) represent pathological outcomes of traumatic or surgical injuries with dysregulated wound healing. We investigated the therapeutic effects and underlying mechanism of autologous chyle fat (ALCF) in HS formation. A thermal injury-induced burn wound model was established in mice. Histopathological alterations, fibrotic deposition, the levels of α-smooth muscle actin (α-SMA), collagen I and collagen III were quantified. To elucidate the mechanism, tumor necrosis factor-stimulated gene-6 (TSG-6) was silenced, and TSG-6, binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), inositol-requiring enzyme 1α (IRE1α), p-IRE1α, c-Jun N-terminal kinase (JNK), and p-JNK were assessed to evaluate endoplasmic reticulum stress (ERS) and downstream signaling. The JNK signaling pathway was pharmacologically activated to validate the IRE1α/JNK axis. Clinically, ALCF injection yielded favorable outcomes. ALCF markedly alleviated fibrosis in burn wound scar tissues and reduced Bip and CHOP, indicating ERS attenuation. ALCF upregulated TSG-6 expression in healing wound tissues, whereas TSG-6 knockdown partially abolished the antifibrotic effects of ALCF. ALCF suppressed IRE1α phosphorylation and JNK activation. Reactivation of the IRE1α/JNK pathway reversed the inhibitory effects of ALCF on ERS and promoted fibrotic deposition. Collectively, ALCF attenuates burn wound fibrosis through TSG-6-mediated suppression of ERS, associated with reduced IRE1α phosphorylation and JNK signaling inhibition.

The phenylalanine hydroxylase (PAH) pathway is an enzymatic pathway focused primarily on the hydroxylation of the amino acid L-phenylalanine (Phe) to L-tyrosine (Tyr). However, the functioning of this pathway can also have significant impacts on other downstream metabolites. In addition, both common and rare genetic variants have been demonstrated to significantly impair PAH pathway function. However, to our knowledge, the comprehensive PAH pathway including influences on related downstream metabolic pathways has not been mapped in an integrative manner. As such, we conducted a narrative review of the literature to describe the comprehensive PAH pathway, including influences on downstream related metabolic pathways, while mapping a visual depiction of these integrative processes. In addition to the hydroxylation of Phe to Tyr, the comprehensive pathway narrative describes Phe metabolism and transport across the blood brain barrier, including competition with other large neutral amino acids, Tyr catabolism, and others. Discussion of the importance of these metabolic processes in the context of PAH genetic variation are also provided. With an increased focus on conducting health research from a systems biology perspective, this work is critical to improving our understanding of the downstream effects of amino acid metabolism and their possible impacts on health outcomes.

Sequence-specific transcription factors (TFs) regulate gene expression in all living organisms. An established function of TFs is to activate or repress transcription of target genes by binding to specific DNA sequence motifs at their promoters. However, in metazoans, accumulating evidence shows widespread TF binding to DNA outside of promoters, binding in the absence of cognate sequence motifs, and functioning without direct DNA binding. Here, we examine findings that support TFs regulating transcription with limited dependence on DNA sequence or at steps post initiation, particularly during promoter-proximal RNA polymerase II (Pol II) pausing. We suggest that mechanisms enabling TF binding outside of cognate sequence motifs, including cofactor- and chromatin-context-dependent binding, condensate-mediated interactions, and contacts with paused Pol II complexes, are critical for coordinating transcription across the genome, and we discuss their potential biological roles. While TFs fundamentally regulate transcription of genes by reading DNA, this function extends beyond promoter-centric and strictly sequence-dependent paradigms.

The alpha subunit of mitochondrial trifunctional protein (αTFP) catalyzes the acylation of monolysocardiolipin (MLCL) to cardiolipin (CL). We determined whether the beta subunit of mitochondrial trifunctional protein (βTFP) impacted the ability of αTFP to promote CL resynthesis from MLCL. Purified recombinant αTFP, but not βTFP, exhibited acylation of MLCL to CL with [1-[14]C]linoleoyl-coenzyme A. Incubation of both αTFP and βTFP together did not alter the ability of αTFP to catalyze the acylation of MLCL to CL with [1-[14]C]linoleoyl-coenzyme A. HeLa cells were transfected with recombinant αTFP, βTFP, or both, then incubated with [1-[14]C]linoleate, and radioactivity incorporated into CL was determined. Expression of αTFP increased [1-[14]C]linoleate incorporation into CL 2-fold (p < 0.05), whereas expression of βTFP did not affect [1-[14]C]linoleate incorporation into CL. Expression of both αTFP and βTFP together increased [1-[14]C]linoleate incorporation into CL to an identical level to that achieved with αTFP alone. Barth syndrome (BTHS) patient lymphoblasts, which exhibit elevated MLCL and reduced CL, were incubated with βTFP inhibitory RNA, and CL mass was determined. Incubation of BTHS lymphoblasts with βTFP inhibitory RNA increased CL mass 1.5-2-fold (p < 0.05). We hypothesize that the βTFP may regulate CL resynthesis in BTHS lymphoblasts.

The direct binding of cAMP to the hyperpolarization-activated cyclic nucleotide-gated channel form 4 (HCN4) protein contributes to autonomic modulation of heart rate. Here, we determine affinity for binding of cyclic nucleotides directly to the cytosolic C-terminus of the HCN4 channel of three disease-linked mutations that are found in the C-linker of the C-terminus, which attaches the more distal binding domain to the pore. Two of these mutations, one in the A'-helix (K530N) and another in the B'-helix (D553N), reduced binding affinity but did not alter the negatively cooperative pattern of binding found in the wild type channel. Finally, a third mutation in the A'-helix (R524Q) did not alter either the pattern or affinity of binding to the cyclic nucleotides despite a dramatic, and previously reported, increase in cAMP potency in the full channel. Our data may be explained by location of each mutation and its interactions with domains external to this region. The data support negatively cooperative binding of cAMP and cGMP to HCN4 and help to identify distinct structural contributions to ligand binding and gating, both of which determine potency.

We aimed to explore the effect and the mechanism of PPP2R2B on cell proliferation, migration, and ferroptosis in breast cancer cells. By bioinformatic analysis and data mining, PPP2R2B was associated with the prognosis and ferroptosis of breast cancer. Breast cancer cells were transfected with PPP2R2B overexpression or PPP2R2B knockdown plasmids, and cell proliferation, apoptosis, migration, and invasion were examined. Moreover, transfected breast cancer cells were treated with ferroptosis inducer, and the relative iron level, Fe[2+] level, MDA level, lipid ROS level, MitoSOX intensity, and fluorescence intensity were detected. Protein expressions of GPX4, ACSL4, and SLC7A11 were evaluated by Western blot. The effect of PPP2R2B on JAK2-STAT3 signaling was studied. Finally, the tumor xenograft model in nude mice was constructed to study the PPP2R2B overexpression on tumor growth in vivo. PPP2R2B was down-regulated in the breast cancer tissues and predicted poor prognosis. PPP2R2B inhibited cell proliferation and induced cell apoptosis. PPP2R2B suppressed cell migration and invasion of MCF-7 and MDA-MB-231 cells. PPP2R2B promoted erastin-induced ferroptosis in breast cancer cells and regulated the expression of GPX4, ACSL4, and SLC7A11. In addition, PPP2R2B inhibited the phosphorylation of JAK2 and STAT3. PPP2R2B also inhibited tumor growth in vivo. PPP2R2B targets the JAK2-STAT3 signaling pathway to regulate cell proliferation, apoptosis, migration, invasion, and ferroptosis in breast cancer cells.

CREB binding protein (CBP) and its homolog E1A binding protein p300 (p300) are crucial lysine acetyltransferases that have been shown to play key roles in various human malignancies. However, the precise functions and regulatory mechanisms of CBP/p300 in hepatocellular carcinoma (HCC) remain to be explored. Herein, we report that the expression levels of CBP and p300 are upregulated in HCC compared to normal tissues, and high CBP expression is associated with poor overall survival based on TCGA data. Combined knockdown of CBP and p300 or treatment with the CBP/p300 histone acetyltransferases (HAT) inhibitor A-485 reduces cell viability and promotes cell death in HCC cell lines. Additionally, inhibition of CBP/p300 activates autophagy, which mediates cell death in HCC cells. Mechanistically, the inhibition of CBP/p300 HAT activity attenuates H3K27ac at Ephrin type-A receptor 2 (EPHA2) super-enhancer and suppresses the expression of EPHA2. EPHA2 overexpression can partially rescue CBP/p300 HAT inhibition-mediated autophagy and loss of cell viability. These findings reveal a novel epigenetic mechanism of CBP/p300 in HCC and identify the CBP/p300 inhibitor A-485 as a promising therapeutic candidate for HCC.