The starting point of the investigation was a molecule with a double life. High mobility group box 1, or HMGB1, is a nuclear protein that normally helps organize DNA and regulate gene transcription inside healthy cells. But when cells are stressed, injured or dying, HMGB1 can be released into the surrounding tissue, where it acts as a danger signal, an alarm molecule that summons and activates the immune system. In cancer, this alarm function can backfire spectacularly. Chronic inflammation is a recognized hallmark of malignancy, and HMGB1 has previously been implicated in promoting tumor growth, invasion and metastasis in cancers ranging from hepatocellular carcinoma to colorectal and pancreatic tumors. What remained unclear was precisely how the oxygen-starved environment inside tumors regulates HMGB1, and what that regulation means for cancers of the oral cavity.

To answer that question, the researchers began with human tissue. They profiled HMGB1 expression in clinical specimens of oral squamous cell carcinoma and compared it with clinicopathological information from the same patients. The results were unambiguous: HMGB1 was constitutively upregulated in the tumor tissues, and the degree of overexpression tracked with clinically ominous features. Tumors with higher HMGB1 levels tended to be larger, and elevated expression was positively associated with lymph node metastasis, the process by which oral cancer cells spread to the neck and dramatically worsen prognosis. When the team constructed Kaplan-Meier survival curves, patients whose tumors expressed the most HMGB1 fared significantly worse than those with lower levels, marking the protein as a candidate prognostic biomarker for the disease.

With the clinical correlation established, the investigators turned to controlled experiments in cell culture to determine whether hypoxia was driving the HMGB1 surge. When oral squamous cell carcinoma cells were exposed to hypoxic conditions, their HMGB1 expression rose markedly. More importantly, the team traced what happened downstream. Hypoxia also increased the levels of NLRP3, a sensor protein that assembles into a multi-subunit complex known as the inflammasome, and of cleaved caspase-1, the proteolytic enzyme that the NLRP3 inflammasome activates. Alongside these inflammatory components, the cells accumulated HIF-1α, the master transcriptional regulator of the hypoxic response. The picture that emerged was of a coordinated pathway: low oxygen elevates HMGB1, and HMGB1 in turn sustains the activation of the NLRP3 inflammasome and its enzymatic output through caspase-1.

The functional consequences of this signaling cascade were tested by silencing HMGB1 in the cancer cells. The results showed that the protein is not merely a passive byproduct of hypoxia but an active driver of malignant behavior. When HMGB1 was knocked down, the hypoxia-induced expression of NLRP3, cleaved caspase-1 and HIF-1α all fell, indicating that HMGB1 sits upstream of the entire axis. Hypoxia alone had markedly enhanced the proliferation of the oral cancer cells, and it also induced pyroptosis, an inflammatory form of programmed cell death executed by gasdermin pores that release interleukin-1 family cytokines. Intriguingly, hypoxia alleviated a G2/M phase arrest in the cell cycle, freeing the cells to progress through division more readily. All of these pro-tumor effects were reversed when HMGB1 was depleted, demonstrating that the molecule is required for hypoxia to exert its full malignant influence on oral cancer cells.

The interplay between hypoxia, inflammation and cell death revealed here is more nuanced than a simple growth signal. Pyroptosis is classically viewed as an anti-cancer process, since it inflames the tumor bed and can alert immune cells to the presence of abnormal tissue. Yet the new findings suggest that in the hypoxic context of oral squamous cell carcinoma, the HMGB1-driven inflammasome activity coexists with, and may even support, enhanced proliferation. The authors propose that the net effect of the pathway is pro-tumor: the same caspase-1 activation that triggers inflammatory death in some cells appears to accompany conditions that release surviving cells from cell cycle constraints and accelerate their expansion. This kind of dual role echoes a broader theme in tumor immunology, in which inflammatory pathways that evolved to fight infection can be co-opted by cancers to remodel their microenvironment in self-serving ways.

Critical evidence came from animal models, where the team could test whether the pathway mattered in the complexity of a living organism rather than a culture dish. In murine xenograft models, in which human oral cancer cells are implanted into mice, knocking down HMGB1 inhibited tumor growth. Separately, the researchers examined the downstream links of the axis using models deficient in NLRP3 or caspase-1, and found that loss of either component delayed the progression of oral cancer. To extend the relevance beyond transplanted tumors, the team also employed a 4-NQO-induced carcinogenesis protocol, a chemically induced model that recapitulates the stepwise development of oral squamous cell carcinoma in mice, from premalignant lesions to invasive cancer. Together, these in vivo experiments established that the HMGB1/NLRP3/caspase-1 axis is not an artifact of cell culture but a functional driver of tumor progression in intact animals.

The study builds on a substantial body of prior work implicating both HMGB1 and the NLRP3 inflammasome in head and neck malignancies. Earlier research from some of the same collaborators had shown that NLRP3 promotes tumor growth and metastasis in oral squamous cell carcinoma, that a microRNA called miR-22 suppresses oral cancer cell proliferation by targeting NLRP3, and that NLRP3 expression in tumor-associated macrophages predicts poor prognosis in head and neck squamous cell carcinoma. Other groups had connected hypoxia-induced HMGB1 to tumor growth in liver cancer through Toll-like receptor 9, and to the self-renewal of glioma stem cells through the receptor RAGE. The new study unifies these threads by placing HMGB1 upstream of the inflammasome in a hypoxia-dependent pathway specific to oral cancer, and by validating the entire axis from clinical specimens through cell biology to animal models.

Therapeutically, the findings point to a strategy that differs from conventional approaches. Because HMGB1 is upregulated in tumor tissue and correlates with poor outcomes, it offers both a biomarker for identifying high-risk patients and a target for intervention. Blocking the pathway at any of its three nodes, whether by neutralizing HMGB1, inhibiting NLRP3 assembly or suppressing caspase-1 activity, delayed cancer progression in the experimental systems. Inflammasome inhibitors are already an active area of drug development for inflammatory and metabolic diseases, and HMGB1-targeting agents have been explored in contexts from acute liver failure to sepsis. The new data suggest that repurposing or refining such inhibitors for oral squamous cell carcinoma, particularly for tumors with documented hypoxia and high HMGB1 expression, could be a viable avenue. The authors also note that hypoxia itself is a known barrier to radiotherapy and immunotherapy, so a pathway that links hypoxia to inflammatory tumor promotion may help explain why some oral cancers resist current treatments.

Oral squamous cell carcinoma remains a disease with a heavy global burden, particularly in regions where tobacco use, alcohol consumption and betel quid chewing are prevalent, and survival rates for advanced disease have improved only modestly in recent decades. A molecular axis that connects the tumor’s oxygen-starved core to inflammatory proliferation, and that is measurable in clinical specimens and targetable in animal models, offers a fresh angle of attack. As with all preclinical research, the distance between xenograft mice and patients is considerable, and questions remain about how best to inhibit the pathway without suppressing the beneficial inflammatory responses that guard against infection. But the study provides a clear mechanistic blueprint: hypoxia raises HMGB1, HMGB1 activates the NLRP3 inflammasome, caspase-1 carries the signal forward, and oral cancer cells proliferate. Interrupting that relay, the researchers conclude, may offer a viable therapeutic strategy for a cancer that urgently needs new options.

Subject of Research: Hypoxia-induced HMGB1/NLRP3/Caspase-1 inflammatory signaling in oral squamous cell carcinoma progression

Article Title: Hypoxia-induced HMGB1/NLRP3/Caspase-1 signaling axis enhances proliferation of oral squamous cell carcinoma

Article References: Wu, K., Zhang, S., Cao, L., Wang, J., Wang, M., Zheng, Z., & Feng, X. (2026). Hypoxia-induced HMGB1/NLRP3/Caspase-1 signaling axis enhances proliferation of oral squamous cell carcinoma. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03632-6

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03632-6

Keywords: oral squamous cell carcinoma, hypoxia, HMGB1, NLRP3 inflammasome, caspase-1, pyroptosis, HIF-1α, tumor microenvironment, prognostic biomarker, inflammation, xenograft model, cancer therapy

The classical pre-metastatic niche paradigm, developed over the past two decades, holds that primary tumors actively prepare distant sites for colonization by releasing soluble factors and extracellular vesicles that travel through the bloodstream and reprogram future metastatic destinations. Bone marrow–derived cells are recruited, blood vessels become leaky and adhesive, immune defenses are suppressed, and the extracellular matrix is degraded and reorganized. What this paradigm does not explain, the review’s authors note, is whether catastrophic systemic inflammation by itself, without any tumor present, can generate similar tissue states. Their answer, assembled from a synthesis of immunological, vascular, and matrix biology, is that it plausibly can, through what they term an Immuno–Vascular–Matrix Triad.

The first arm of the triad is immunological. Sepsis unleashes a storm of damage-associated molecular patterns, including high-mobility group box 1, mitochondrial DNA, and adenosine triphosphate, which flood the circulation as injured cells rupture. These alarmins engage Toll-like receptors, most notably TLR4, on immune and stromal cells, igniting signaling cascades that sustain inflammation well beyond the initial insult. In the acute phase, neutrophils respond with explosive production of neutrophil extracellular traps, web-like lattices of DNA and antimicrobial proteins that normally help contain pathogens. When this NETosis becomes dysregulated, it feeds immunothrombosis, promoting platelet activation and diffuse microthrombosis that choke off capillary beds and create focal pockets of hypoxia throughout the body’s tissues.

Hypoxia is not a passive consequence in this framework but an active remodeling signal. Oxygen-starved regions stabilize hypoxia-inducible factor-1α, a transcription factor that reprograms cellular metabolism and drives angiogenic and pro-adhesive gene expression, echoing the low-oxygen conditions that characterize developing metastatic niches. Meanwhile, the immune system enters a prolonged state of dysfunction that the authors describe as immunodisruption. Lymphopenia, the depletion of circulating lymphocytes, can persist long after a patient has technically recovered. Surviving T cells become exhausted through checkpoint pathways such as PD-1 and CTLA-4, the same molecular brakes that tumors exploit to escape immune attack. Regulatory T cells expand, dampening inflammatory responses but also blunting anti-tumor surveillance, and monocytes lose expression of human leukocyte antigen-DR, impairing their ability to present antigens and coordinate adaptive immunity.

The second arm of the triad concerns the vasculature. Sepsis inflicts direct injury on the endothelium, the single-cell lining of blood vessels that normally acts as a selective barrier and a gatekeeper for immune cell traffic. Glycocalyx degradation, endothelial activation, and increased vascular permeability allow plasma proteins and cells to leak into surrounding tissue. In the pre-metastatic niche literature, vascular leakiness and endothelial hyperadhesiveness are hallmark features that facilitate the extravasation of circulating tumor cells. The review argues that post-sepsis endothelium displays a functionally analogous phenotype: vessels that are more permeable, more adhesive to circulating myeloid cells, and less selective about what crosses them. Persistent recruitment of myeloid cells into tissues, a process sustained by altered chemokine signaling, mirrors the way tumors co-opt bone marrow–derived cells to prepare metastatic sites.

The third arm involves the extracellular matrix, the fibrous scaffold that gives tissues their architecture and mechanical properties. During sepsis, mesenchymal stromal cells and inflammatory extracellular vesicles drive the release of matrix metalloproteinases, enzymes that cleave collagen, laminin, and fibronectin. The result is a matrix that is mechanically unstable, abnormally permeable, and richly pro-adhesive, presenting cryptic binding sites and altered stiffness cues to any cell that encounters it. In established cancer biology, matrix remodeling of this kind lowers the barriers to tumor cell invasion and supports the survival of newly arrived malignant cells. The review proposes that a post-sepsis matrix, transiently or perhaps chronically remodeled, could create comparable conditions of systemic permissiveness, lowering tissue resistance to aberrant cellular persistence of many kinds.

What makes the framework scientifically interesting is its convergence logic. None of the individual components is novel; immunothrombosis, endothelial activation, lymphopenia, and matrix degradation are each well documented in sepsis research. The review’s contribution is to assemble them into a coordinated model and to point out that their combined output, endothelial hyperadhesiveness, reduced immune selectivity, persistent myeloid recruitment, and increased tissue susceptibility, is precisely the functional signature that tumor biologists use to define a pre-metastatic niche. In this reading, sepsis does not cause cancer directly, and the authors are careful to frame the triad as a host-conditioned state of biological plausibility rather than an oncogenic event. The claim is about vulnerability and permissiveness, not causation, and it is explicitly presented as a generator of testable hypotheses rather than a settled conclusion.

That framing matters, because the epidemiological question of whether sepsis survivors face elevated cancer risk remains open and contested in the broader literature. What the review offers is a mechanistic roadmap for investigating that question rigorously. If post-sepsis patients carry measurable, persistent signatures of niche-like priming, elevated circulating markers of endothelial activation, sustained shifts in lymphocyte subsets, altered matrix turnover products, then longitudinal cohort studies could track whether these signatures predict subsequent malignancy diagnoses. Such biomarkers would also serve a second purpose: stratifying the growing population of sepsis survivors, whose numbers have grown as intensive care keeps more patients alive, by their biological risk profile rather than by clinical appearance alone.

The clinical implications extend to post-sepsis recovery monitoring more broadly. Post-sepsis syndrome, encompassing cognitive decline, physical disability, and renewed susceptibility to infection, is increasingly recognized as a major public health burden, yet follow-up care for survivors remains fragmentary in most health systems. If the Immuno–Vascular–Matrix Triad proves measurable in routine clinical practice, it could anchor a new category of surveillance: not merely checking whether organs have recovered their function, but assessing whether tissues have returned to a state of immunological and structural integrity. Interventions that restore immune competence, protect the endothelium, or modulate matrix remodeling could then be evaluated for their ability to reverse primed tissue states before they translate into disease.

The authors are candid about the limits of their synthesis. It is a review, built on mechanistic reasoning across literatures that rarely speak to one another, and it does not present direct experimental evidence that sepsis-primed tissues accept circulating tumor cells more readily. Animal models that induce sepsis and then challenge animals with tumor cell lines would be an obvious next step, as would careful analysis of cancer incidence in large sepsis registries with adequate follow-up and control for confounders such as smoking, comorbidities, and post-sepsis surveillance bias, since survivors undergo more medical attention and thus more diagnosis. Even so, the conceptual payoff is considerable: it reframes sepsis not only as an acute crisis to survive but as a systemic remodeling event whose biological echoes may persist, and it hands researchers a concrete, three-part framework for testing whether the body’s fiercest inflammatory storm can quietly prepare the ground for its next great challenge.

Subject of Research: Post-sepsis tissue remodeling as a mimic of the pre-metastatic niche through immune, vascular, and extracellular matrix alterations

Article Title: Sepsis as a pre-metastatic niche mimic: post-sepsis microenvironmental priming through an Immuno–Vascular–Matrix Triad

Article References: Izquierdo-Condoy, J. S., Saavedra-Torres, J. S., Nati-Castillo, H. A., Gil, J. C., García-Aguilera, M. F., Alexander-León, H. A., Lara Puello, I. M., Vargas Saltos, M., & Ortiz-Prado, E. (2026). Sepsis as a pre-metastatic niche mimic: post-sepsis microenvironmental priming through an Immuno–Vascular–Matrix Triad. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08951-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08951-z

Keywords: sepsis, pre-metastatic niche, metastasis, immunothrombosis, immunodisruption, extracellular matrix remodeling, endothelial dysfunction, HMGB1, neutrophil extracellular traps, HIF-1α, matrix metalloproteinases, cancer microenvironment

The significance of the finding lies in the tumor microenvironment. Colorectal cancer progression has long been associated with elevated levels of TGF-β in the blood of patients, and previous work by the same group had suggested that colon cancer cells themselves can secrete interleukin-6 and TGF-β2 in ways that may undermine chemotherapy. Earlier studies have also shown that TGF-β2 serves as a prognostic biomarker correlated with immune cell infiltration in colorectal cancer, and that higher frequencies of SMAD4 mutations occur in colorectal cancers with distant metastasis. What remained unclear was precisely how the presence of this ligand changes the cellular response to a cytotoxic drug, and whether it steers cells toward one resistance mechanism over another.

To answer that question, the researchers treated Colo205 cells with doxorubicin alone or in combination with TGF-β2 for seven days, then tracked a battery of cellular and molecular readouts over time. Cell proliferation was inhibited after the first day of treatment, while measurable loss of viability and cytotoxicity emerged after day three. Crucially, by the end of the seven-day window, no comparable loss of viability persisted, indicating that a fraction of the treated cells had adapted to the drug rather than succumbed to it. That temporal pattern, initial damage followed by recovery, is the classic fingerprint of acquired chemoresistance developing in a cell population under selective pressure.

One of the earliest and most striking differences appeared in the co-treated group. The multidrug resistance protein 1, known as MDR1, an efflux pump that expels chemotherapeutic agents from cells, was significantly elevated at both the gene and protein levels after just one day, but only in the cells that received both doxorubicin and TGF-β2. By days three and seven, all treatment groups showed elevation of MDR1, but the early, ligand-dependent surge suggests that TGF-β2 accelerates the deployment of the pump. The team confirmed this functionally using rhodamine 123 efflux assays, which measure how efficiently cells pump out a fluorescent dye handled by the same transporter, and assessed MDR1 at the gene, cell-surface, and total protein levels to build a consistent picture of enhanced drug export.

Beyond pumping drugs out, the surviving cells appeared to change their internal chemistry. The researchers detected induction of autophagy, the cellular recycling process in which cells digest their own components to survive stress, using three complementary approaches: acridine orange staining to visualize acidic organelles, monodansylcadaverine staining to label autophagic vacuoles, and measurement of the LC3II/I protein ratio, a standard molecular marker of autophagic flux. Autophagy has previously been implicated in doxorubicin resistance in breast cancer and hepatocellular carcinoma models, and HMGB1, the high mobility group box 1 protein, is known to drive autophagy-mediated resistance to doxorubicin through the AMPK/mTOR pathway in liver cancer cells. The new study places TGF-β2 upstream of this machinery in colon cancer.

The phenotypic shift extended to cell identity. After seven days of treatment, the co-treated cells showed increased expression of mesenchymal and stem cell markers, alongside downregulation of the Dab2 protein, a regulator linked to TGF-β signaling whose loss has been documented in pancreatic cancer progression and whose cleavage is known to regulate TGF-β-induced autophagy. The gain of mesenchymal traits, a process called epithelial-mesenchymal transition, is a well-established route by which epithelial tumors acquire both invasive capacity and drug tolerance. Notably, prior research has shown that SMAD4 mutations do not preclude epithelial-mesenchymal transition in colorectal cancer, which helps explain how a SMAD4-mutant line like Colo205 can still execute these TGF-β2-driven programs.

Perhaps the most unexpected result concerned HMGB1 and the transcription factor NF-κB. In the TGF-β2-containing groups, HMGB1 levels were significantly decreased, and the researchers observed arrest of NF-κB p65 nuclear translocation, meaning the inflammatory transcription factor failed to move into the nucleus where it would normally activate resistance genes. This is counterintuitive on the surface, since HMGB1 and NF-κB are often associated with pro-survival signaling and MDR1 regulation, and NF-κB inhibitors have been shown to revert multidrug resistance in breast cancer cells. The finding suggests that in this SMAD4-mutant, metastatic context, the TGF-β2 ligand reroutes the resistance program away from the canonical HMGB1-NF-κB axis and toward an autophagy- and stemness-dominated pathway, even though the study’s title frames HMGB1 as a participant in the process.

The authors interpret this constellation of results as evidence that the presence of the TGF-β2 ligand might determine which resistance pathway doxorubicin-treated metastatic colon cancer cells adopt. In practical terms, this matters because resistance is not a single switch but a branching decision tree, and different branches respond to different therapeutic countermeasures. If a patient’s tumor microenvironment is rich in TGF-β2, the cancer cells may be primed to survive doxorubicin through autophagy and stem-like phenotypes rather than through the routes a clinician might otherwise expect. Prior clinical research has explored TGF-β blockade as a strategy, including the anti-TGF-β monoclonal antibody fresolimumab in advanced melanoma and renal cell carcinoma, and animal work has shown that TGF-β blockade can normalize tumor stroma and improve drug distribution in breast carcinoma models.

The study also connects to a broader literature on colorectal cancer drug resistance. Doxorubicin, though more classically associated with breast cancer, leukemia, and sarcoma treatment, has served as a valuable experimental tool in colon cancer models, and previous work from the same laboratory demonstrated that TGF-β2 aggravates doxorubicin-induced chemoresistance in a Duke’s type B colon adenocarcinoma cell line through non-apoptotic cell death. Other groups have shown that chemoresistance to doxorubicin induces epithelial-mesenchymal transition via upregulation of TGF-β signaling in HCT116 colon cancer cells, and that targeting the stem cell marker CD133 reverses drug resistance via the AKT/NF-κB/MDR1 pathway in colorectal cancer. The Colo205 findings add a ligand-dependent dimension to this picture, implying that the same drug can push cells down different resistance routes depending on the signaling molecules floating in their surroundings.

As with all cell-line studies, the caveats are real. Colo205 is a single metastatic line with a defined SMAD4 mutation, and the seven-day treatment window captures early adaptation rather than the long evolution of resistance in a patient over months of therapy. The data were generated with established assays, including the MTT-based colorimetric method for proliferation and cytotoxicity introduced decades ago, and the autophagy measurements were cross-validated with multiple stains and the LC3II/I ratio, which strengthens confidence in the core observations. The authors report no conflicts of interest, and the datasets are available from the corresponding author upon reasonable request. The work was supported by a DST-INSPIRE fellowship from the Department of Science and Technology, Government of India, and conducted at SRM Institute of Science and Technology in Tamil Nadu.

The immediate value of the study is conceptual: it argues that chemoresistance in metastatic colon cancer is context-dependent, shaped by paracrine and autocrine TGF-β2 signaling, and funneled through autophagy, efflux pump upregulation, and stem-like reprogramming in ways that a SMAD4 mutation does not prevent. If follow-up work in additional cell lines, organoids, and ultimately patient tumors confirms that TGF-β2 levels predict which resistance pathway dominates, the finding could inform combination strategies that pair cytotoxic drugs with autophagy inhibitors or TGF-β pathway blockers, timed to the biology of the individual tumor. For now, the Colo205 experiments provide a mechanistic map of how a single signaling molecule in the tumor microenvironment can tip the balance between cell death and cell survival under chemotherapy, and they underscore why the microenvironment deserves equal billing with the cancer cell itself in the ongoing effort to make treatment stick.

Subject of Research: TGF-β2-driven autophagy-mediated doxorubicin resistance in metastatic colon cancer cells

Article Title: TGF-β2 promotes autophagy-mediated resistance to doxorubicin in metastatic colon cancer cells via HMGB1

Article References: Sritharan, S., Jayavelu, T., & Sivalingam, N. (2026). TGF-β2 promotes autophagy-mediated resistance to doxorubicin in metastatic colon cancer cells via HMGB1. Medical Oncology, 43(11), Article 298. https://doi.org/10.1007/s12032-026-03404-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03404-5

Keywords: TGF-β2, doxorubicin, chemoresistance, autophagy, HMGB1, MDR1, colorectal cancer, NF-κB, SMAD4, epithelial-mesenchymal transition, cancer stem cells, tumor microenvironment

The research team, working at the Laboratory Animal Center of Shanghai University of Traditional Chinese Medicine, set out to answer two linked questions. First, could they establish a stable and reproducible rat model of lung injury driven by myocardial ischemia and reperfusion? Second, could pretreatment with electroacupuncture reduce that injury, and if so, did the HMGB1/RAGE pathway, a pair of molecules long implicated in acute lung inflammation, sit at the center of the mechanism? Their answer to both questions, based on a series of five carefully controlled experiments in male Sprague-Dawley rats, was yes.

Building the model required calibrating the injury. The researchers ligated the left anterior descending coronary artery in anesthetized rats for 30 minutes, 45 minutes, or one hour, then released the snare to allow 24 hours of reperfusion, confirming ischemia by visible cyanosis of the ventricular wall and ST-segment elevation on the electrocardiogram. Only the one-hour ischemia protocol produced consistent, measurable lung damage. In those animals, arterial oxygen partial pressure and the oxygenation index fell significantly, the alveolar-arterial oxygen gradient rose, and the lung wet-to-dry weight ratio, a standard gauge of pulmonary edema, climbed sharply. Under the microscope, the lungs showed alveolar collapse, hemorrhage, thickened septa, and dense inflammatory infiltration, and immunostaining revealed abundant cleaved caspase-3, a hallmark of apoptosis. Shorter ischemic periods produced weaker or statistically insignificant changes, establishing one hour of ischemia followed by 24 hours of reperfusion as the reliable model.

With the model in hand, the team turned to electroacupuncture. They stimulated two classical acupoints, Zusanli (ST36) on the hind limb and Feishu (BL13) on the back near the lungs, using a 2/20 Hz dense-disperse waveform for 30 minutes per session. The critical variable was timing. A single 30-minute session immediately before ischemia did essentially nothing: blood gas values, edema measures, injury scores, and apoptotic cell counts in that group were indistinguishable from the untreated ischemia-reperfusion group. But when the same stimulation was repeated over three consecutive days before the procedure, the picture changed dramatically. Oxygenation improved, the wet-to-dry ratio dropped, lung injury scores fell, and cleaved caspase-3 staining diminished significantly compared with injured animals that received no pretreatment.

The protective effect was accompanied by a clear anti-inflammatory signature. Quantitative PCR showed that ischemia-reperfusion drove up the messenger RNA of the pro-inflammatory cytokines IL-1β and IL-6 and the chemokines CXCL1 and CXCL2 in lung tissue. Three days of electroacupuncture pretreatment significantly reduced all four transcripts at four hours of reperfusion, with IL-6 and CXCL1 still suppressed at 24 hours. Immunohistochemistry told a parallel story at the cellular level: myeloperoxidase-positive neutrophils and F4/80-positive macrophages, the two dominant infiltrating populations, flooded the injured lungs after reperfusion but were markedly fewer in the pretreated animals at both early and late time points.

The molecular centerpiece of the study was HMGB1, a nuclear non-histone protein that escapes from stressed cells and acts as a danger signal when it binds transmembrane receptors, most notably RAGE and the Toll-like receptors. Western blotting and PCR revealed that ischemia-reperfusion significantly increased both HMGB1 and RAGE in lung tissue, and electroacupuncture pretreatment brought both back down at four and 24 hours of reperfusion. Because HMGB1 is known to recruit and activate inflammatory cells in many forms of acute lung injury, the authors reasoned that this axis could be the plausible bridge between the systemic inflammatory surge triggered by cardiac ischemia and the pulmonary damage that follows.

A key question was where the lung HMGB1 actually came from. The injured heart itself is an obvious suspect. Yet when the researchers measured HMGB1 expression in heart tissue, they found it elevated only in the earliest phase of inflammation and essentially normal by 24 hours of reperfusion, precisely when lung HMGB1 remained high. Moreover, electroacupuncture reduced lung HMGB1 without changing myocardial infarct size, measured by triphenyltetrazolium chloride staining, indicating that the treatment was not simply shrinking the cardiac wound and thereby sending fewer danger signals. The accumulating HMGB1 in the lungs, the data suggested, was generated locally rather than imported from the heart.

To test causality more directly, the team delivered recombinant HMGB1 protein directly into the lungs via intubation-mediated intratracheal administration before reperfusion. Adding the protein to injured animals worsened respiratory dysfunction, edema, and histological injury to some degree. More tellingly, in rats that had received the three-day electroacupuncture pretreatment, intratracheal recombinant HMGB1 significantly raised lung HMGB1 and RAGE expression, lowered oxygenation indices, increased the wet-to-dry ratio, worsened injury scores, and boosted apoptotic cell counts. In other words, flooding the lungs with the very molecule the therapy suppresses partially reversed its benefits, evidence that HMGB1 is not merely a bystander but a functional target of the electroacupuncture effect.

The authors are candid about the limits of their work. The validation relied on recombinant protein challenge rather than genetic knockout, which leaves some causal uncertainty, and the sample sizes were small, with five rats per group. All experiments were conducted in male animals, and no clinical data exist yet to confirm that the findings translate to patients awaiting cardiac surgery. Larger, multicenter human studies will be needed before electroacupuncture pretreatment can be recommended as a standard element of perioperative lung protection.

Even so, the study adds a compelling piece to a growing body of evidence that neuromodulation through acupuncture-like stimulation can precondition distant organs against surgical stress. Previous work has shown electroacupuncture protecting the lungs during cardiopulmonary bypass by dampening inflammasome activation and oxidative stress pathways, and the new findings extend that logic to the specific HMGB1/RAGE axis in the setting of myocardial ischemia and reperfusion. If the mechanism holds in humans, a low-side-effect intervention delivered in the days before surgery could help reduce the burden of postoperative pulmonary complications, aligning with the principles of enhanced recovery after surgery and broadening the toolkit of perioperative organ protection.

Subject of Research: Electroacupuncture pretreatment and protection against myocardial ischemia/reperfusion-induced lung injury via the HMGB1/RAGE pathway in rats

Article Title: Electroacupuncture pretreatment alleviates myocardial ischemia/reperfusion‐induced lung injury by inhibiting the expression of HMGB1/RAGE in male rats

Article References: Xie, C., Zhang, J., Zhang, Y., Chi, H., Yong, Y., & Song, J. (2026). Electroacupuncture pretreatment alleviates myocardial ischemia/reperfusion‐induced lung injury by inhibiting the expression of HMGB1 / RAGE in male rats. Physiological Reports, 14(18), Article e71066. https://doi.org/10.14814/phy2.71066

Image Credits: AI Generated

DOI: 10.14814/phy2.71066

Keywords: electroacupuncture, myocardial ischemia-reperfusion, lung injury, HMGB1, RAGE, inflammation, acute lung injury, cardiac surgery, pulmonary complications, rat model, preconditioning, enhanced recovery after surgery

Hepatocellular carcinoma remains one of the deadliest malignancies worldwide, ranking among the leading causes of cancer-related death. Its lethality stems largely from two clinical realities: a strong tendency to spread beyond the liver, and a stubborn resistance to conventional chemotherapeutic agents. Even as immunotherapy and targeted agents reshape the treatment landscape, many patients progress rapidly, and the molecular drivers of that progression have remained only partially mapped. The new findings add a critical piece to that map, positioning ApoA2 not as a passive biomarker but as an active participant in the tumor’s malignant behavior.

Apolipoproteins are best known for their role in lipid metabolism, shuttling cholesterol and triglycerides through the circulation. ApoA2 is a major constituent of HDL particles, and circulating levels of the protein have previously been associated with metabolic syndrome, cardiovascular disease, and, intriguingly, with altered risk profiles in several cancers. Epidemiological observations had hinted at connections between ApoA2 abundance and tumor behavior, but the mechanistic basis for such a link was unclear. The new study set out to determine whether ApoA2 is merely a correlate of disease severity or a genuine contributor to it.

Using hepatocellular carcinoma cell lines, animal models, and clinical tissue samples, the researchers found that ApoA2 expression is elevated in aggressive tumors and correlates with poor prognosis. When the team manipulated ApoA2 levels in laboratory models, the consequences were striking. Increasing ApoA2 enhanced the migratory and invasive capacity of cancer cells, while suppressing it markedly reduced metastatic potential. In mouse models of liver cancer, tumors with high ApoA2 activity spread more readily and responded poorly to chemotherapy, whereas lowering ApoA2 restored drug sensitivity and curtailed tumor dissemination.

The mechanistic heart of the paper lies in the HMGB1/IL-17A axis. HMGB1, or high-mobility group box 1, is a DNA-binding protein that normally resides in the nucleus, where it helps regulate gene expression and genome architecture. When cells are stressed, damaged, or activated by inflammatory signals, HMGB1 can be released into the extracellular space, where it acts as a danger signal, or alarmin, binding to receptors such as RAGE and Toll-like receptors to ignite inflammatory responses. The study demonstrates that ApoA2 promotes the secretion of HMGB1 from hepatocellular carcinoma cells, converting an intracellular housekeeping protein into an extracellular inflammatory messenger.

Once outside the cell, HMGB1 sets off a chain reaction. The researchers show that extracellular HMGB1 stimulates the production of interleukin-17A, a pro-inflammatory cytokine classically associated with Th17 immune cells but increasingly recognized as a product of the tumor microenvironment itself. IL-17A is known to fuel chronic inflammation, promote angiogenesis, and foster an immunosuppressive milieu that favors tumor growth. In this context, the ApoA2-HMGB1-IL-17A circuit appears to create a self-reinforcing inflammatory loop within and around the tumor, one that simultaneously drives cells toward invasive behavior and shields them from the cytotoxic effects of chemotherapeutic drugs.

The drug resistance component of the findings is particularly consequential. Chemotherapy for hepatocellular carcinoma has long been hampered by modest response rates, and understanding why some tumors shrug off treatment is a central question in the field. The study provides evidence that the HMGB1/IL-17A pathway activated by ApoA2 helps cancer cells survive drug-induced stress, likely through inflammatory survival signaling and alterations in the tumor microenvironment that blunt drug efficacy. When the researchers interfered with the axis, blocking HMGB1 or neutralizing IL-17A, the resistance phenotype weakened, suggesting that each node in the pathway represents a potential therapeutic target.

From a translational standpoint, the work carries several implications. First, ApoA2 could serve as a biomarker to identify patients whose tumors are predisposed to metastasis and treatment failure, allowing clinicians to stratify therapy more aggressively from the outset. Second, existing drugs or biologics that target IL-17A, some of which are already approved for inflammatory diseases such as psoriasis, could potentially be repurposed or adapted for hepatocellular carcinoma, either alone or in combination with chemotherapy or immunotherapy. Third, the identification of HMGB1 as a pivotal intermediary offers another intervention point, and HMGB1 inhibitors are an area of active pharmaceutical development.

The findings also resonate with a broader conceptual shift in cancer biology: the recognition that metabolic proteins and inflammatory circuits are deeply intertwined with malignant progression. Tumors do not evolve in isolation; they co-opt the body’s lipid transport machinery, danger-sensing systems, and immune signaling networks to advance their own agenda. The ApoA2/HMGB1/IL-17A axis is a vivid example of this co-option, linking a routine component of blood lipid particles to the inflammatory engine that powers metastasis and treatment resistance. It underscores why chronic inflammation of the liver, whether from viral hepatitis, alcohol, or fatty liver disease, creates such fertile ground for cancer, and why interrupting inflammatory signaling may be as important as attacking the cancer cells directly.

As with any preclinical study, important questions remain before the findings can change clinical practice. The precise molecular steps by which ApoA2 triggers HMGB1 release, the relative contributions of tumor cells versus immune cells to IL-17A production, and the safety of targeting this axis in patients with underlying liver disease all require further investigation. Human validation in large, prospective cohorts will be essential to confirm ApoA2’s prognostic value. Nevertheless, the study delivers a compelling and mechanistically grounded case that a familiar blood protein is an unexpected architect of liver cancer aggression, and it opens a concrete path toward therapies that could strip hepatocellular carcinoma of two of its most dangerous weapons: the ability to spread and the ability to survive treatment.

Subject of Research: The role of apolipoprotein A2 in promoting metastasis and drug resistance in hepatocellular carcinoma through the HMGB1/IL-17A inflammatory signaling axis.

Article Title: ApoA2 promotes tumor metastasis and drug resistance in hepatocellular carcinoma by activating the HMGB1/IL-17A axis

Article References: Fu, Z., Zhu, F., Fu, Z., Wang, C., Guan, T., Yuan, Y., Zhang, S., & Zhang, T. (2026). ApoA2 promotes tumor metastasis and drug resistance in hepatocellular carcinoma by activating the HMGB1/IL-17A axis. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03317-2

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03317-2

Keywords: ApoA2, hepatocellular carcinoma, HMGB1, interleukin-17A, metastasis, drug resistance, liver cancer, inflammation, tumor microenvironment, biomarker, cytokine signaling, chemotherapy