Astragalus Compounds Reshape Immune Cells to Fight Inflammation and Cancer

Macrophage polarization—the dynamic shift between pro-inflammatory M1 and anti-inflammatory/reparative M2 phenotypes—sits at the center of numerous chronic and acute diseases. When dysregulated, M1 macrophages drive tissue damage through TNF-α and IL-6 secretion, while insufficient M2 activity impairs repair via reduced IL-10 signaling. Precisely controlling this balance is a major therapeutic challenge, and natural compounds are increasingly viewed as promising multi-target modulators.

This systematic review, drawing on PubMed, Google Scholar, and SciFinder literature from 2013–2025, comprehensively examines how AS-IV and its hydrolysate CAG—both derived from the traditional Chinese herb Astragalus membranaceus (Huangqi)—regulate macrophage polarization. The biosynthetic pathway of AS-IV has now been fully elucidated, involving a mevalonate-derived triterpenoid skeleton modified by CYP450 enzymes and glycosyltransferases. CAG is produced from AS-IV via hydrolysis, with enzymatic biotransformation achieving up to 94.5% molar conversion efficiency under optimized conditions.

Across disease models, AS-IV suppresses M1 polarization and promotes M2 phenotypes through several critical signaling nodes: TLR4/NF-κB (inflammatory diseases and sepsis), PI3K-AKT/mTORC1 (cancer and metabolic disease), AMPK (metabolic syndrome and atherosclerosis), PPARγ (adipose tissue inflammation), JAK-STAT, and NLRP3 inflammasome pathways. In sepsis models, AS-IV inhibits macrophage hyperactivation; in atherosclerosis, it reduces foam cell formation via TAK1 signaling; in Parkinson's disease, CAG suppresses microglial NLRP3 inflammasome activation and promotes autophagy. In cancer contexts, these compounds modulate tumor-associated macrophage (TAM) polarization to reduce immunosuppression and enhance antitumor immunity.

A significant translational barrier for both compounds is low oral bioavailability due to poor water solubility and rapid metabolism. The review highlights nanotechnology-based delivery platforms—including nanoparticles, liposomes, and hydrogels—as transformative solutions that improve pharmacokinetics, enable targeted tissue delivery, and expand clinical applicability. Looking ahead, the authors propose that combining CRISPR-based gene editing, computer-aided drug design (CADD), and advanced nanoformulations could optimize AS-IV and CAG efficacy and accelerate their path from bench to bedside.

While the breadth of evidence is compelling, the review acknowledges that most data come from in vitro and animal studies, with limited human clinical trial data. The complexity of macrophage biology in vivo, potential off-target effects, and the challenge of standardizing natural product preparations remain important caveats for clinical translation.