The research, led by Wanqiu Huang and Jinjing Ni together with colleagues at Shanghai Jiao Tong University School of Medicine and collaborating institutions, focuses on a histone modification known as H2BK16ac. This tag refers to the acetylation of lysine 16 on histone H2B, one of the proteins around which DNA is wound. Acetylation of histone tails generally loosens the chromatin structure, making genes more accessible to the transcription machinery. When the researchers examined macrophages infected with Salmonella, they found that this acetylation mark on H2BK16 was actively removed. The deacetylation was carried out by two enzymes, HDAC1 and HDAC3, which strip acetyl groups from histones and thereby tighten chromatin at specific genomic locations.

The consequence of this chromatin tightening was the transcriptional silencing of a gene called Id3, which encodes Inhibitor of Differentiation 3. ID3 is a member of the helix-loop-helix protein family and is known to influence the behavior of various immune cells, but its role in macrophage-mediated antibacterial defense had not been clearly defined. The new study shows that when Salmonella drives H2BK16 deacetylation through HDAC1 and HDAC3, the Id3 gene is switched off, and macrophages lose an important layer of antimicrobial capacity. This finding places ID3 at the center of an infection-induced epigenetic pathway that directly shapes how macrophages respond to bacterial challenge.

To establish that ID3 genuinely strengthens macrophage defenses, the team performed both loss-of-function and gain-of-function experiments. When ID3 was removed or reduced, macrophages showed a weakened inflammatory response and diminished antimicrobial activity. Conversely, when ID3 was increased, macrophages displayed enhanced antibacterial function. These results demonstrate that ID3 is not a passive bystander in the infection response but an active contributor to the macrophage arsenal against invading bacteria.

The mechanistic heart of the study lies in how ID3 controls the expression of another protein, Z-DNA binding protein 1, commonly abbreviated as ZBP1. ZBP1 is a sensor that recognizes certain nucleic acid structures and participates in immune signaling. The researchers discovered that a transcription factor called E2A binds to the ZBP1 gene and represses its transcription. ID3 counteracts this repression by sequestering E2A, effectively pulling it away from the ZBP1 promoter. With E2A occupied by ID3, the ZBP1 gene is free to be transcribed, and macrophages maintain robust ZBP1 expression. This sequestration mechanism reveals a precise molecular handoff in which ID3 acts as a decoy to relieve transcriptional braking on an antimicrobial effector gene.

The in vivo relevance of this circuit was tested in mice engineered to lack Id3 specifically in myeloid cells, the lineage that includes macrophages. When these myeloid-specific Id3-deficient mice were infected with Salmonella, they carried higher bacterial burdens and suffered greater pathological damage than control animals. This outcome confirms that the ID3-ZBP1 axis is not merely a cell-culture curiosity but a functional component of antibacterial immunity in living organisms. The data suggest that the integrity of this epigenetic pathway determines how effectively the host can contain systemic bacterial spread.

Perhaps the most translational aspect of the study involves a pharmacological intervention. The researchers treated infected mice with MS-275, an inhibitor of histone deacetylases that targets HDAC1 among other class I enzymes. Administration of MS-275 restored the H2BK16ac mark, reactivated the Id3 gene, and thereby rebuilt the ID3-ZBP1 signaling axis. In practical terms, the drug reversed the epigenetic silencing that Salmonella had imposed on macrophages. Mice receiving this treatment showed amelioration of systemic Salmonella infection, demonstrating that pharmacologically reopening the chromatin at Id3 can translate into meaningful protection against bacterial disease.

These findings carry several implications for the broader field of infection biology. First, they establish that pathogens do not merely evade immune detection; they actively reshape the epigenetic landscape of host immune cells to disable specific defense genes. The Salmonella-driven deacetylation of H2BK16 represents a concrete example of how bacterial infection can hijack the host’s own chromatin-modifying enzymes to silence protective transcriptional programs. Second, the study identifies ID3 as a previously underappreciated regulator of macrophage immunity, bridging histone acetylation status to the expression of a nucleic acid sensor involved in antimicrobial signaling. Third, the demonstration that an HDAC inhibitor can restore this axis in vivo suggests a therapeutic window in which epigenetic drugs, originally developed for oncology, might be repurposed as adjunct treatments for severe bacterial infections.

The work also raises questions that will likely drive future research. It remains to be seen whether other pathogens employ similar strategies to silence Id3 or related immune regulators through histone deacetylation. The precise kinetics of HDAC1 and HDAC3 recruitment to the Id3 locus during infection, and whether additional chromatin marks cooperate with H2BK16ac in this process, are areas that warrant deeper investigation. Furthermore, because ZBP1 has been implicated in antiviral as well as antibacterial pathways, the ID3-E2A-ZBP1 circuit could have relevance beyond Salmonella, potentially influencing how macrophages respond to a wider spectrum of infectious threats. The study by Huang, Ni, and colleagues thus opens a new line of inquiry into how epigenetic therapies might bolster innate immunity at a time when antibiotic resistance continues to limit conventional treatment options.

Subject of Research: Infection-driven epigenetic regulation of macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article Title: Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article References: Huang, W., Ni, J., Tang, H., Chen, Y., Zhou, T., Yu, J., Wang, Z., Wen, B., Yan, H., Wang, C., Tao, J., Lu, J., Zhao, G.-P., Wang, D., & Yao, Y.-F. (2026). Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06432-6

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06432-6

Keywords: macrophage, innate immunity, epigenetics, histone acetylation, H2BK16ac, ID3, ZBP1, Salmonella, HDAC1, HDAC3, E2A, MS-275

The technical centerpiece of the work is a family of fluorescent biosensors called iNap, which fluoresce in proportion to NADPH concentration and can be targeted to specific cellular compartments. When the researchers expressed these sensors in adult mouse cardiomyocytes, they observed that swimming and running exercise elevated the NADPH signal in the cytosol while leaving the mitochondrial pool untouched. This compartmental specificity matters, because cytosolic and mitochondrial NADPH fluxes are known to be independently regulated, and it points the finger away from mitochondrial transhydrogenase and toward cytosolic sources. Among those sources, the pentose phosphate pathway, or PPP, stood out: a glucose-shunting branch of metabolism whose rate-limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), strips electrons from glucose-6-phosphate and deposits them onto NADP+ to make NADPH.

The causal chain was established through a series of loss-of-function experiments. When the team inhibited PPP activity or depleted cytosolic NADPH in mice, the heart’s response to exercise was blunted: the characteristic enlargement of cardiomyocytes that normally accompanies training failed to materialize. Conversely, the study showed that NADPH itself is a driver of cardiomyocyte growth, acting by inhibiting the HDAC3/C/EBPβ pathway—a signaling axis previously implicated in the control of exercise-induced cardiac growth. In other words, the reducing equivalents manufactured by the PPP do more than keep reactive oxygen species in check; they directly tune an epigenetic and transcriptional program that tells heart cells to grow in a coordinated, physiological manner rather than in the maladaptive fashion seen in disease.

The protective side of the story emerged from mouse models of acute ischemia–reperfusion injury, a scenario that unfolds in millions of patients each year when a blocked coronary artery is reopened and the sudden return of oxygen floods the tissue with reactive oxygen species. Mice with an exercise-activated PPP/NADPH pathway suffered measurably less injury from a subsequent ischemia–reperfusion challenge, and this protection persisted: four weeks after the insult, heart function remained significantly preserved compared with sedentary controls. The mechanism appears to be twofold. First, abundant NADPH sustains the glutathione and thioredoxin antioxidant systems that neutralize the oxidative burst of reperfusion. Second, by suppressing HDAC3 activity, NADPH restrains the transcriptional changes that push stressed cardiomyocytes toward death and maladaptive remodeling.

What makes the study more than an elegant piece of mechanistic cardiology is its drug-discovery angle. The researchers screened 310 Tibetan medicinal compounds for the ability to raise intracellular NADPH, and one molecule rose to the top: lyciumspermidine-0527, a spermidine derivative derived from a plant used in traditional Tibetan medicine. Biochemical and structural analyses showed that this compound directly activates G6PD, the rate-limiting enzyme of the pentose phosphate pathway, stabilizing the enzyme’s active dimeric form. In cultured cardiomyocytes and in living mice, lyciumspermidine-0527 elevated cytosolic NADPH, promoted cardiomyocyte growth, and—most strikingly—alleviated ischemia–reperfusion injury to a degree that rivaled exercise itself.

Safety data accompanying the compound were encouraging. Across a range of doses in vitro and in vivo, lyciumspermidine-0527 did not significantly induce cell death in the heart, and histological examination of heart, liver, lung, kidney, and brain tissue showed no overt toxicity. The compound also maintained redox homeostasis in cardiomyocytes, consistent with its proposed mechanism of boosting, rather than overwhelming, the cell’s antioxidant buffering capacity. Genetic confirmation followed: when G6PD was knocked down, the protective effects of the compound vanished, placing G6PD squarely upstream of the observed benefit and ruling out major off-target explanations for the phenotype.

Conceptually, the findings reframe physiological cardiac hypertrophy as a metabolic checkpoint phenomenon. The healthy heart’s enlargement in response to exercise has long been distinguished from the pathological hypertrophy of hypertension or heart failure by its reversibility and preserved function, but the molecular gatekeepers separating the two states have been only partially mapped. By demonstrating that PPP-derived NADPH is required for exercise-induced growth and simultaneously protective against injury, the study positions a single metabolite as a checkpoint that integrates the demand for biosynthesis (NADPH feeds fatty acid and nucleotide production), antioxidant defense (NADPH powers glutathione reductase), and epigenetic regulation (NADPH inhibits the HDAC3–Ncor complex). Exercise, in this view, is a metabolic intervention, and its cardiac benefits can be recapitulated—at least in mice—by pharmacologically opening a single metabolic valve.

The translational horizon is tantalizing but cautious. Lyciumspermidine-0527 is not yet a drug, and the leap from mouse models of surgically induced ischemia–reperfusion to human myocardial infarction is considerable. G6PD activity is a double-edged sword: the same pathway that supports antioxidant defense in cardiomyocytes also supports nucleotide synthesis and growth in cancer cells, raising questions about systemic effects that would need careful evaluation in longer-term studies. Nonetheless, the identification of a small molecule that directly activates G6PD offers a starting point for medicinal chemistry, and the iNap biosensor toolkit the team deployed provides a template for screening compounds by their ability to raise NADPH in specific subcellular compartments rather than by crude proxies.

For now, the study’s most immediate contribution is conceptual clarity. It explains, in mechanistic terms, why the exercising heart grows well and withstands injury better, connecting the dots from a transcription factor (SP1-driven G6PD expression), through a metabolic flux (the pentose phosphate pathway), to a redox cofactor (cytosolic NADPH), and finally to an epigenetic effector (HDAC3/C/EBPβ) and a clinical phenotype (preserved function after reperfusion). It also validates a natural-product-inspired approach to finding exercise mimetics for the heart. If the PPP/NADPH axis holds up in larger preclinical models, the prospect of a pill that trains the heart’s metabolism—conferring some of exercise’s cardioprotection on patients who cannot exercise—moves from metaphor to plausible pipeline.

Subject of Research: Pentose phosphate pathway-derived NADPH as a metabolic checkpoint regulating exercise-induced physiological cardiac hypertrophy and protection against ischemia–reperfusion injury

Article Title: Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia–reperfusion injury in the heart

Article References: Wu, D., Chen, T., Dong, X., Li, H., Cheng, Z., Li, H., Chao, Y., Li, F., Yin, Y., Guo, F., Xu, X., Zhang, Y., Ning, K., Fu, X., Bian, Y., Ma, F., Ritterhoff, J., Wang, W., & Hu, Q. (2026). Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia–reperfusion injury in the heart. Nature Metabolism. https://doi.org/10.1038/s42255-026-01587-9

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01587-9

Keywords: NADPH, pentose phosphate pathway, cardiac hypertrophy, exercise, ischemia-reperfusion injury, glucose-6-phosphate dehydrogenase, cardiomyocytes, HDAC3, lyciumspermidine-0527, redox homeostasis, cardiac metabolism, Nature Metabolism

Nuclear receptors are ligand-activated transcription factors that bind specific DNA sequences and switch target genes on or off in response to small molecules. Several members of this superfamily are central players in bile acid biology. The farnesoid X receptor, or FXR, is the canonical bile acid sensor, activated by chenodeoxycholic acid and related species, and it feeds back to suppress the enzyme CYP7A1, the rate-limiting step in classical bile acid synthesis, largely through induction of the repressive nuclear receptor SHP. The pregnane X receptor and the constitutive androstane receptor act as xenobiotic and bile acid sensors that induce detoxification and export pathways, protecting hepatocytes from bile acid overload. The liver X receptor links oxysterol sensing to bile acid synthesis via CYP7A1 induction, while the retinoid X receptor serves as a common dimerization partner for many of these receptors. Each of these receptors, however, does not act alone: their output depends on the coregulatory proteins they recruit to DNA.

This is where SMRT enters the picture. SMRT, short for silencing mediator of retinoid and thyroid hormone receptors and also known as NCOR2, is one of the two major corepressors of the nuclear receptor superfamily, the other being its paralog NCoR1. In the absence of activating ligand, many nuclear receptors bind SMRT, which in turn recruits large multiprotein complexes containing histone deacetylases such as HDAC3, along with transducin beta-like proteins and other chromatin-modifying enzymes. These complexes deacetylate histones and maintain local chromatin in a transcriptionally repressive state. When ligand binds, the receptor undergoes a conformational change, releases the corepressor, and recruits coactivators instead. This ligand-dependent corepressor exchange is the fundamental switch that converts receptor binding into transcriptional activation, and it means that the abundance, localization, and post-translational modification state of SMRT directly shapes how strongly and how quickly target genes respond to their ligands.

For bile acid homeostasis specifically, SMRT has been implicated in the regulation of nearly every major nuclear receptor pathway in the hepatocyte and the enterocyte. In the FXR pathway, corepressor exchange at FXR target promoters such as SHP, BSEP, and the intestinal FGF15/FGF19 locus determines the strength of the enterohepatic feedback signal that restrains CYP7A1 expression. In the CAR and PXR pathways, SMRT occupancy at promoters of detoxification genes such as CYP2B and CYP3A, and at bile acid exporters, governs the inducible defense against cholestatic injury. In the LXR pathway, corepressor association with LXR/RXR heterodimers at the CYP7A1 promoter influences the balance between bile acid synthesis and cholesterol efflux. The review emphasizes that these are not independent circuits but an integrated network in which SMRT acts as a shared rheostat, tuning gene expression across pathways in response to nutritional state, circadian cues, and inflammatory signals.

The physiological consequences of disrupting this corepressor function are substantial. Animal studies over the past two decades have shown that perturbing corepressor complexes, particularly the SMRT- and NCoR-associated HDAC3 complex, produces profound metabolic phenotypes. Liver-specific deletion of HDAC3 in mice leads to marked alterations in lipid and bile acid metabolism, reflecting the loss of repressive chromatin marks at metabolic gene promoters. Similarly, mice with impaired corepressor recruitment to specific nuclear receptors display altered bile acid pool sizes, changes in the hydrophobicity of the bile acid pool, and altered sensitivity to cholestatic liver injury. Because bile acids themselves are cytotoxic at high concentrations and pro-carcinogenic when they accumulate in the intestine, the fidelity of this corepressor-mediated feedback is a matter of liver and gut health, not merely transcriptional housekeeping.

The review also highlights the emerging role of SMRT in the enterohepatic circulation itself. Bile acids are secreted into bile, stored in the gallbladder, released into the duodenum after meals, reabsorbed in the terminal ileum, and returned to the liver through portal blood. At each step, nuclear receptors in enterocytes and hepatocytes sense the local bile acid concentration and adjust transporter expression accordingly. SMRT-dependent repression and derepression at these transporter genes, including ASBT in the ileum and NTCP and BSEP in the liver, helps set the flux rate of the entire circulation. Disruption of this tuning can shift the bile acid pool toward more hydrophobic species, which are stronger FXR agonists but also more damaging to membranes, thereby creating a feedback loop that links corepressor function to both signaling intensity and cytotoxic risk.

Beyond classical bile acid metabolism, the review connects SMRT-regulated nuclear receptor signaling to systemic metabolic disease. Bile acids activate FXR and the membrane receptor TGR5 to influence glucose homeostasis, insulin sensitivity, thermogenesis in brown adipose tissue, and energy expenditure. The bile acid pool is also a major determinant of gut microbiome composition, and the microbiome in turn modifies bile acids through deconjugation and dehydroxylation, generating secondary bile acids with distinct receptor specificities. Because SMRT shapes the expression of the enzymes and transporters that determine which bile acids circulate and in what amounts, corepressor function sits upstream of this entire host-microbe metabolic axis. The authors argue that this positions SMRT as a potential node at which diet, microbiome, and nuclear receptor pharmacology converge, with implications for nonalcoholic fatty liver disease, cholestasis, metabolic syndrome, and gastrointestinal cancers.

Therapeutically, the framework has clear implications. FXR agonists such as obeticholic acid are already approved for certain cholestatic conditions and are being evaluated for metabolic liver disease, while dual and selective modulators of FXR, TGR5 agonists, and CAR activators are in various stages of development. The review suggests that the efficacy of such ligands depends not only on receptor binding but on the corepressor and coactivator landscape of the target tissue. A ligand that promotes efficient corepressor release will produce a stronger transcriptional response than one that does not, and tissue-specific differences in SMRT abundance could explain variable drug responses between patients and between liver and intestine. This perspective points toward a second generation of nuclear receptor therapeutics designed with coregulator exchange in mind, and toward biomarkers based on coregulator occupancy that could predict which patients will benefit from bile acid-directed therapies.

The review closes by identifying open questions that will define the next phase of the field. These include mapping the genome-wide occupancy of SMRT at bile acid-related loci in a cell-type-specific manner, determining how post-translational modifications of SMRT such as phosphorylation, ubiquitination, and sumoylation respond to nutritional and inflammatory signals, and clarifying how SMRT and NCoR1 divide labor between hepatocytes, cholangiocytes, and intestinal epithelial cells. Single-cell and chromatin profiling technologies are expected to accelerate this work, as are degrader and PROTAC approaches that can selectively manipulate corepressor complexes. What is already clear, the authors contend, is that bile acid homeostasis cannot be understood as a simple ligand-receptor-feedback circuit. It is a coregulator-dependent system in which SMRT provides the repressive counterweight that gives nuclear receptor signaling its dynamic range, its tissue specificity, and its resilience against metabolic and toxicological stress.

Subject of Research: SMRT corepressor regulation of nuclear receptor signaling in bile acid homeostasis

Article Title: SMRT regulation of nuclear receptors orchestrates bile acid homeostasis

Article References: Kim, K., Fang, S., Hong, S.-H., Cho, H., Leblanc, M., Jacinto, S., Schnabl, B., Atkins, A. R., Yu, R. T., Liddle, C., Truitt, M. L., Fan, W., Lee, C. M., Downes, M., & Evans, R. M. (2026). SMRT regulation of nuclear receptors orchestrates bile acid homeostasis. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01823-y

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01823-y

Keywords: SMRT, NCOR2, nuclear receptors, bile acids, FXR, CYP7A1, cholestasis, HDAC3, liver metabolism, enterohepatic circulation, corepressors, metabolic disease