The rationale for the combination rests on the complementary profiles of the two drugs. Azvudine, known chemically as FNC, is a nucleoside reverse transcriptase inhibitor approved in China for HIV treatment and later authorized for COVID-19. As an analogue, it is incorporated by viral polymerases and terminates RNA synthesis, acting directly on the SARS-CoV-2 RNA-dependent RNA polymerase. Carrimycin, by contrast, is a macrolide derived from the engineered antibiotic compound 4″-O-isovalerylspiramycin. Macrolides are best known as antibacterials, but several members of the class display immunomodulatory and anti-inflammatory properties, and Carrimycin has previously shown antiviral activity against coronaviruses. Pairing a direct-acting polymerase inhibitor with an agent that modulates host responses is an appealing strategy precisely because evolving SARS-CoV-2 variants have begun to erode the effectiveness of replication-targeted monotherapy.

To test the concept, the team turned to rhesus macaques, which remain among the most faithful animal models of human COVID-19 because they develop viral pneumonia, radiographic abnormalities, and immune responses that closely mirror clinical disease. Animals were inoculated intratracheally with SARS-CoV-2 and then treated orally for seven days with Carrimycin at 9 milligrams per kilogram, Azvudine at 0.07 milligrams per kilogram, or the two drugs together. The researchers then tracked viral loads, lung pathology, immune responses, and gut microbiota across the treatment groups, conducting the work in an animal biosafety level 3 facility under protocols approved by the institutional animal care committee.

The antiviral results were clear-cut. Both monotherapies significantly inhibited SARS-CoV-2 replication, but the combination produced additive effects, driving viral loads down further in both throat swabs and lung tissue. That pattern matters because viral burden in the lower respiratory tract correlates with disease severity and onward transmission risk. Notably, the authors reported no significant side effects in the treated animals, an important consideration for a combination intended for clinical use, since drug-drug interactions and cumulative toxicity often limit real-world combination regimens.

Lung protection was assessed by chest imaging and histopathology, and here the combination again outperformed either drug alone. Monotherapy reduced ground-glass opacities, the hazy areas on chest scans that reflect fluid and inflammatory infiltration of lung tissue, and mitigated focal interstitial pneumonia, the inflammation of the tissue between air sacs that characterizes severe COVID-19. The combination treatment demonstrated superior efficacy on both measures, suggesting that blunting viral replication while simultaneously damping host inflammation preserves lung architecture more effectively than either intervention alone.

To understand how the combination reshaped the lung environment, the researchers performed transcriptomic profiling and immunofluorescence staining of lung tissue. Gene expression analysis revealed enhanced immunomodulation under combination therapy, including suppression of neutrophil degranulation, a process in which activated neutrophils release enzymes and antimicrobial proteins that, when excessive, damage surrounding tissue and contribute to acute lung injury. The combination also increased populations of CD19-positive B cells and CD3-positive T cells, the cornerstones of adaptive humoral and cellular immunity, while decreasing CD68-positive macrophages, whose accumulation in the lung is associated with sustained inflammation.

At the molecular level, combination therapy downregulated pro-inflammatory and apoptotic markers, pointing to reduced inflammatory signaling and less programmed cell death in infected lung tissue. Taken together, these findings suggest the combination does more than lower viral numbers; it shifts the lung immune landscape away from the maladaptive innate hyperinflammation seen in severe COVID-19 and toward a more effective adaptive response. That distinction is clinically significant, because mortality in severe COVID-19 is driven as much by immunopathology as by the virus itself, and therapies that address both axes have been sought since the beginning of the pandemic.

The study also uncovered a difference between the two drugs that monotherapy comparisons alone would have missed. Carrimycin, but not Azvudine, increased gut bacteria that produce short-chain fatty acids, metabolites with well-documented anti-inflammatory and immune-regulatory effects, and decreased harmful pathogens previously associated with COVID-19 progression. The gut-lung axis, the bidirectional communication between intestinal microbes and respiratory immunity, has emerged as a contributor to COVID-19 outcomes, and dysbiosis has been linked to worse disease. A drug that simultaneously acts on the lung and restores a favorable microbiome composition could therefore offer benefits beyond direct antiviral activity, potentially supporting recovery and reducing secondary complications.

The authors conclude that the Carrimycin-Azvudine combination showed superior efficacy in suppressing viral replication, alleviating lung injury, and correcting immune and inflammatory dysregulation, with Carrimycin providing additional gut microbiota benefits. They position the pairing as a promising therapeutic strategy against COVID-19 and its complications, particularly in a landscape where ongoing viral mutation, emerging resistance mutations, inadequate immunomodulation, and suboptimal organ protection limit existing antiviral options. The work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, and the CAMS Innovation Fund for Medical Sciences.

As with any preclinical animal study, the path from macaques to patients requires clinical validation, including pharmacokinetic confirmation of the doses used, human safety data for the combination, and efficacy trials in infected populations. Nevertheless, the study offers a mechanistically grounded template for next-generation COVID-19 therapy: a direct-acting antiviral paired with an immunomodulatory and microbiome-friendly partner, evaluated with the full toolkit of modern virology, imaging, transcriptomics, and metagenomics. If the additive antiviral and lung-protective effects observed here translate to humans, the combination could address precisely the shortcomings, resistance, inflammation, and organ damage, that have constrained single-drug approaches throughout the pandemic.

Subject of Research: Combination antiviral therapy with Carrimycin and Azvudine against SARS-CoV-2 infection in rhesus macaques

Article Title: Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2

Article References: Li, H., Liu, Y., Xue, J., Li, J., Xu, J., Dong, B., Wang, T., Peng, X., Che, Y., Jiang, J., & Peng, Z. (2026). Better antiviral and lung-protective effects of Carrimycin in combination with Azvudine in rhesus macaques infected with SARS-CoV-2. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08933-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08933-1

Keywords: SARS-CoV-2, Carrimycin, Azvudine, combination therapy, rhesus macaques, lung injury, immunoinflammatory regulation, gut microbiota, antivirals, macrolides, COVID-19, translational medicine

Senescent cells are cells that have permanently stopped dividing but refuse to die. They secrete a toxic cocktail of inflammatory molecules known as the senescence-associated secretory phenotype, or SASP, and even small numbers of transplanted senescent cells can accelerate aging in mice. Conversely, drugs that clear these cells, called senolytics, have extended healthspan and improved age-related phenotypes in animal studies. The landmark dasatinib-plus-quercetin combination, along with fisetin and UBX0101, established proof of concept, but small-molecule senolytics lack precision and have produced disappointing clinical results accompanied by side effects such as diarrhea, anemia, and rash.

Immunotherapy offers a sharper alternative. uPAR, the receptor for urokinase-type plasminogen activator, is broadly expressed on senescent cells and tumor cells but largely absent from healthy young tissue. CAR T cells engineered against uPAR have already reversed senescence-driven pathologies in mice, including liver fibrosis and metabolic dysfunction. Yet the approach carries risks: high doses of uPAR CAR T cells caused hypothermia, weight loss, and elevated cytokines in mice, and CAR T cells, once infused, expand unpredictably from patient to patient, making their toxicity hard to titrate. The team therefore turned to a bispecific T-cell engager, or BiTE, a soluble antibody construct that recruits a patient’s own T cells to target cells and vanishes from the bloodstream within days, allowing dosing to be adjusted or halted at will.

The engineered molecule, named hGFD-CD3, links the GFD domain of human uPA, the natural ligand of uPAR, to an anti-CD3 antibody fragment derived from the clinically tested drug acapatamab, with a non-functional Fc region added to extend its half-life. In laboratory dishes, the engager bound uPAR-positive senescent human lung fibroblasts and CD3-positive T cells simultaneously, killing senescent cells with an IC50 of just 0.015 nanomolar, a potency the authors attribute to the moderate, natural affinity of the ligand-based recognition domain. Young cells and cells treated with a control construct lacking the GFD domain were spared. Treated T cells upregulated the activation markers CD25 and CD69 and released granzyme along with the inflammatory cytokines TNF-alpha and IFN-gamma.

The in vivo story was more complicated, and it is here that the study makes its most consequential discovery. When aged mice received a high dose of the mouse version of the engager, 1 milligram per kilogram, they died within 24 hours; 0.3 milligrams per kilogram caused ruffled fur, anorexia, and a 20- to 30-fold surge in the liver enzymes AST and ALT. Histopathology pointed squarely at the liver. The reason, the team found, is that liver sinusoidal endothelial cells are among the very few non-hematopoietic cells in the body that express uPAR. Unlike the continuous, basement-membrane-backed vessels of the lung and kidney, liver sinusoids are fenestrated and lack a basement membrane, so widespread destruction of their endothelial lining collapses the microcirculation and injures hepatocytes. In uPAR knockout mice, the engager caused no liver damage at all, proving the toxicity was uPAR-dependent. The same hepatotoxicity appeared with uPAR CAR T cells, even in macrophage-deficient NSG mice, overturning the earlier hypothesis that macrophage activation was to blame.

Crucially, that toxicity proved monitorable and avoidable. At 0.1 milligrams per kilogram, a dose that left liver enzymes and tissues unremarkable, weekly mGFD-CD3 treatment for three weeks significantly reduced uPAR, p16INK4a, and p21 expression across tissues of 22-month-old mice, decreased senescence-associated beta-galactosidase staining in fat, liver, and lung, and suppressed SASP gene expression in liver RNA-sequencing analysis. The engager physically bridged T cells to senescent cells in tissue sections, activated peripheral T cells, and reduced uPAR-positive macrophages. Cytokine rises were modest, roughly twofold, far below cytokine-storm thresholds, and returned to baseline after treatment stopped.

The long-term benefits in mice were striking. Three months after starting treatment, circulating SASP factors had fallen, liver and lung fibrosis had eased, glomerulosclerosis was attenuated, and bone remodeling shifted favorably, with fewer osteoclasts and more active osteoblasts. After six months, treated mice showed better grip strength, treadmill endurance, walking speed, and hanging endurance, along with denser skeletal muscle fibers, less trabecular bone loss, a higher lean-mass fraction, healthier subcutaneous fat distribution, lower fasting glucose, and improved glucose tolerance and insulin sensitivity. Serum transaminases remained within normal ranges throughout, and no tissue showed pathological abnormalities.

The team then crossed the species barrier. In 24-year-old rhesus macaques, roughly equivalent to a 70-year-old human, a dose-escalation trial showed no abnormalities at 10 or 20 micrograms per kilogram, while 40 micrograms per kilogram produced anorexia and a 50 to 100 percent rise in AST and ALT, though still within the normal reference range. At the selected 20-microgram-per-kilogram dose given every three days, two of three macaques tolerated treatment without clinical signs; one showed transient anorexia and transaminase elevations that peaked at 108 U/L for AST and 134 U/L for ALT and cleared within three days. Temporary drops in white blood cells, neutrophils, lymphocytes, and blood pressure all rebounded by day three, a pattern consistent with T-cell migration into tissues rather than destructive depletion, and these fluctuations diminished with repeated dosing.

Over 90 days of follow-up, senescent cell burden in subcutaneous fat, measured by beta-galactosidase staining, fell by day 42, and uPAR, p16INK4a, and p21 expression dropped in fat, muscle, and skin before drifting back up by day 90 as senescent cells slowly re-accumulated. Serum SASP levels fell in parallel, and immune-cell gene signatures declined, indicating reduced tissue inflammation. The macaque with the heaviest senescent burden was the one with the strongest transient enzyme and cytokine responses, reinforcing the authors’ proposal that liver function tests can serve as a practical, biomarker-guided safety gauge for uPAR-targeted senolytics. Because senescent cells are rare, non-proliferative, and take months to return, the team argues that intermittent, low-dose regimens, potentially as infrequent as twice yearly, could impose minimal treatment burden. They caution that for preventive anti-aging use the risk-benefit balance demands careful evaluation, and suggest that diseases with clear unmet need, such as chronic kidney disease, Alzheimer’s disease, and liver fibrosis, may be the most sensible first indications for clinical translation.

Subject of Research: Senolytic immunotherapy targeting uPAR with a bispecific T-cell engager in aged mice and non-human primates

Article Title: uPAR‐Targeting T Cell Engager Exerts Senolytic Effects in Mice and Non‐Human Primates With Serum Aminotransferase Activity as a Safety Monitor

Article References: Deng, J., Zeng, X., Guo, J., Li, L., Zou, S., Liu, N., He, S., Yan, L., Wang, Q., Zhu, Y., Wang, B., Yang, D., Lv, L., & Zhao, X. (2026). uPAR ‐Targeting T Cell Engager Exerts Senolytic Effects in Mice and Non‐Human Primates With Serum Aminotransferase Activity as a Safety Monitor. Aging Cell, 25(10), Article e70742. https://doi.org/10.1111/acel.70742

Image Credits: AI Generated

DOI: 10.1111/acel.70742

Keywords: senolytics, cellular senescence, uPAR, T-cell engager, BiTE, aging, hepatotoxicity, aminotransferases, CAR T cells, rhesus macaques, SASP, liver sinusoidal endothelial cells