Immune ‘Don’t Eat Me’ Protein CD47 Drives Chemotherapy-Induced Heart Aging in Male Mice

One of the most widely used and life-saving chemotherapy drugs in the world carries a hidden cost: it can push the heart into a premature state of aging. Doxorubicin, an anthracycline agent deployed against breast cancer, lymphomas, leukemias, and many solid tumors, is notorious for causing cardiotoxicity that can surface years after treatment ends. Now, a new study published in Physiological Reports has identified an unexpected molecular culprit in this process, a transmembrane glycoprotein called CD47, best known as the immune checkpoint molecule that tells macrophages not to devour healthy cells. The research, conducted by a team at Xinxiang Medical University in China, shows that CD47 expression climbs in aging hearts and in doxorubicin-damaged cardiac tissue, and that blocking this protein with a clinical antibody candidate can ease senescence-like changes and preserve heart function in male mice.

The significance of the finding lies in how it connects two previously separate threads of biology. CD47 has long been studied in oncology and immunology because it broadcasts a so-called “don’t eat me” signal. When CD47 on a cell’s surface engages its receptor, signal regulatory protein alpha (SIRPα), on macrophages and other myeloid cells, it triggers inhibitory pathways that suppress phagocytosis and efferocytosis, the orderly clearance of dead and dying cells. Cancer cells exploit this signal to evade immune surveillance, which is why anti-CD47 antibodies are being developed as cancer therapeutics. Separately, CD47 also binds thrombospondin-1 and integrins, pathways that regulate nitric oxide signaling, vascular tone, oxidative stress, and cell survival. Prior work has linked CD47 upregulation to cardiac hypertrophy, fibrosis, ischemia-reperfusion injury, and atherosclerosis, while CD47 inhibition has been shown to protect cardiac function in several models.

What remained unknown was whether CD47 participates in cardiac aging itself, particularly the accelerated aging induced by chemotherapy. Clues had been accumulating. In skeletal muscle stem cells, CD47 levels rise with age, and as senescence markers such as beta-galactosidase activity increase, the density of CD47 on the cell surface climbs in parallel, forming what researchers have described as a molecular signature of aging. Aberrant CD47 expression has also been documented in aged fibroblasts, epithelial cells, and red blood cells. Because doxorubicin inflicts a characteristic cascade of injuries on the myocardium, including DNA intercalation, interference with topoisomerase-II-dependent DNA repair, chromatin disruption through nucleosome destabilization and histone eviction, mitochondrial dysfunction, oxidative stress, impaired autophagy, and inflammatory activation, the Chinese team hypothesized that CD47 might serve as the underexplored link between these upstream insults and persistent, age-like cardiac remodeling.

To test this, the researchers first turned to public transcriptomic databases. They analyzed two independent cardiac aging datasets from the Gene Expression Omnibus: a rat dataset (GSE173360) comparing six-month-old adult males with 24-month-old aged animals, and a mouse dataset (GSE225576) comparing young and aged hearts. In both species, CD47 expression was significantly elevated in aged heart tissue, and functional enrichment analysis of the differentially expressed genes revealed alterations in metabolic and myocardial contraction-related pathways. The consistency across two mammalian species suggested that CD47 upregulation is a conserved feature of cardiac aging rather than a quirk of one model system.

The team then built a doxorubicin-induced cardiac aging model in six-month-old male C57BL/6J mice. Animals received weekly intraperitoneal injections of doxorubicin at 2.5 milligrams per kilogram for six consecutive weeks, a regimen designed to mimic the cumulative cardiac stress seen in chemotherapy patients. Molecular analysis confirmed that the model worked: mRNA levels of canonical aging markers, including p53, p16, p21, and the proliferation marker KI67, were markedly elevated in the hearts of doxorubicin-treated mice. Crucially, both the mRNA and protein levels of CD47 were significantly increased in these aged hearts, as demonstrated by quantitative PCR, western blotting, and immunofluorescent staining of cardiac tissue sections.

With the model established, the researchers introduced their therapeutic intervention: ligufalimab, also known as AK117, a humanized IgG4 monoclonal antibody that targets CD47 and blocks its interaction with SIRPα without altering CD47 expression itself. Mice receiving doxorubicin plus weekly ligufalimab at 1 milligram per kilogram showed a striking molecular shift. Expression of the senescence effectors p21 and p16 declined significantly in the heart, indicating that CD47 blockade was not merely improving hemodynamics but was actually dampening the senescence-associated signaling that underlies age-like cardiac remodeling. Echocardiographic assessment, performed after the final dose under pentobarbital anesthesia, told a parallel story. Left ventricular fractional shortening and ejection fraction, the standard functional measures of cardiac pumping performance, dropped sharply in doxorubicin-treated mice compared with saline controls, but ligufalimab co-treatment significantly improved both parameters.

To probe whether the effect was conserved in human cells, the team turned to AC16 cardiomyocytes, a human cardiac cell line derived from a male donor. Cells treated with 0.1 micromolar doxorubicin for 48 hours developed a clear senescence-like phenotype, with p16 and p21 mRNA rising steeply and CD47 mRNA and protein increasing in parallel. When ligufalimab at 0.1 micrograms per milliliter was added alongside the chemotherapy, p21 fell at both the mRNA and protein levels, p16 declined at the mRNA level, and senescence-associated beta-galactosidase staining revealed a notable reduction in cellular aging. The convergence of results from living mouse hearts and cultured human cardiomyocytes strengthens the argument that the protective effect is not species-specific or model-dependent, and it points toward genuine translational relevance.

Mechanistically, the authors propose a compelling explanation centered on the CD47-SIRPα axis. During doxorubicin-induced cardiac injury, upregulated CD47 on stressed or senescent cardiomyocytes may shield those cells from macrophage-mediated clearance, allowing damaged cells to linger and continue broadcasting inflammatory and profibrotic signals throughout the myocardium. By blocking CD47, ligufalimab may restore the removal of injured and senescent cells, limit chronic inflammatory amplification, and thereby interrupt the self-reinforcing loop that converts acute chemotherapy injury into persistent age-like remodeling. The observed reduction in p53, p16, and p21 after CD47 blockade is consistent with this interpretation, suggesting that the antibody attenuates senescence-associated signaling itself rather than simply propping up contractile performance. The finding also reframes CD47 as more than an immune checkpoint molecule: it appears to function as a stress-responsive regulator that integrates cellular damage, immune clearance, and cardiovascular remodeling.

The authors are careful to note that important questions remain before this science can reach the clinic. The downstream mechanisms are not yet fully defined; future work should directly assess SIRPα-dependent efferocytosis, thrombospondin-1/CD47 signaling, mitochondrial function, reactive oxygen species production, inflammatory cytokines, and senescence-associated secretory factors. It is also unclear whether the benefits of anti-CD47 therapy are immune-mediated, intrinsic to cardiac cells, or both, and cell-specific genetic models, macrophage-depletion experiments, and efferocytosis assays will be needed to disentangle these contributions. Because CD47 is broadly expressed and plays essential roles in immune surveillance and red blood cell clearance, clinical translation will demand careful optimization of treatment timing, dose, tissue specificity, and safety. The researchers suggest that transient or cardiac-targeted CD47 inhibition might retain cardioprotective effects while minimizing systemic adverse effects. They also acknowledge that the study focused on male mice and on the heart alone, leaving open whether CD47 regulates aging in other organs and in female animals. Even so, the study marks a notable step: it identifies CD47 as both a potential biomarker of cardiac aging and a druggable contributor to chemotherapy-induced cardiac decline, raising the prospect that oncologists might one day protect the aging heart while still unleashing doxorubicin’s full anticancer power.

Subject of Research: The role of CD47 in doxorubicin-induced cardiac aging and its blockade as a cardioprotective strategy in male mice

Article Title: CD47 is a regulator in doxorubicin‐induced cardiac aging in male mice

Article References: Yan, A., Mai, R., Cao, T., Duan, C., Liu, S., & Wang, X. (2026). CD47 is a regulator in doxorubicin‐induced cardiac aging in male mice. Physiological Reports, 14(18), Article e71111. https://doi.org/10.14814/phy2.71111

Image Credits: AI Generated

DOI: 10.14814/phy2.71111

Keywords: CD47, doxorubicin, cardiac aging, cardiotoxicity, senescence, ligufalimab, SIRPα, efferocytosis, cardiomyocytes, echocardiography, chemotherapy, heart failure