# How a Compound from Traditional Chinese Medicine Fights Liver Cancer: Understanding Astragaloside-IV (AS-IV) Therapy for Hepatocellular Carcinoma

Liver cancer, specifically hepatocellular carcinoma (HCC), remains one of the world's deadliest cancers, causing over 760,000 deaths per year worldwide. A systematic review published in *BMC Cancer* in 2025 examined 16 scientific studies to understand exactly how astragaloside-IV (AS-IV), a compound extracted from the traditional Chinese herb *Astragalus membranaceus* (Huangqi), fights this aggressive disease. The review found that AS-IV attacks liver cancer through at least six distinct mechanisms: it slows cancer cell growth, blocks cancer spread, triggers cancer cell death, strengthens the immune system's defenses, reverses drug resistance, and cuts off the blood supply that tumors need to survive. These findings are promising, but the researchers emphasize that large, well-designed human clinical trials are still needed before AS-IV can be recommended as a mainstream liver cancer treatment.

# How a Compound from Traditional Chinese Medicine Fights Liver Cancer: Understanding Astragaloside-IV (AS-IV) Therapy for Hepatocellular Carcinoma

## Table of Contents

- Key Points
- Background: Understanding Hepatocellular Carcinoma and the Search for New Treatments
- What Is Astragaloside-IV (AS-IV)?
- Study Methods: How This Systematic Review Was Conducted
- Key Findings: The 16 Studies at a Glance
- Mechanism 1: Inhibiting Cancer Cell Growth (Proliferation)
- Mechanism 2: Blocking Cancer Spread (Metastasis and Invasion)
- Mechanism 3: Triggering Cancer Cell Death (Apoptosis)
- Mechanism 4: Strengthening the Immune System (Immunomodulation)
- Mechanism 5: Reversing Drug Resistance and Enhancing Chemotherapy
- Mechanism 6: Cutting Off the Tumor's Blood Supply (Angiogenesis)
- Study Quality: Risk of Bias Assessment
- Clinical Implications: What This Means for Patients
- Limitations of This Research
- Recommendations for Patients and Researchers
- Frequently Asked Questions
- Source Information

## Key Points

- Astragaloside-IV is a compound from Astragalus membranaceus (Huangqi), studied for liver cancer.
- A 2025 review analyzed 16 studies, mostly in cells and animals, not patients.
- Six anti-cancer mechanisms were found, including blocking growth, spread, and blood supply.
- Astragaloside-IV may reverse drug resistance, but only in laboratory studies so far.
- Large, well-designed human clinical trials are needed before recommending it as treatment.

## Background: Understanding Hepatocellular Carcinoma and the Search for New Treatments

Hepatocellular carcinoma (HCC) — the most common type of primary liver cancer — is the **sixth most common malignancy worldwide** and ranks among the **top three causes of cancer-related death** when measured by overall disease burden. According to estimates from the WHO International Agency for Research on Cancer, HCC accounted for **over 870,000 new cases and 760,000 deaths globally in 2022**.

Despite major advances in diagnosis and treatment over recent years, the outlook for advanced HCC patients remains poor. Innovations have included improvements in surgical techniques, optimized radiation therapy strategies, the development of new chemotherapy drugs, precision-targeted therapies, breakthroughs in immunotherapy, and the adoption of multidisciplinary care models. Yet survival rates for advanced disease are still suboptimal, with only limited improvements in long-term prognosis.

Adding to the challenge, HCC has a high recurrence rate and a significant risk of distant metastasis. This creates what researchers describe as a **"treatment-relapse-retreatment" vicious cycle** that places an immense burden on patients, their families, and entire healthcare systems.

Because of these difficulties, the search for new therapeutic strategies and novel anti-cancer agents has become an urgent priority. Natural plant resources are increasingly viewed as a **"green treasure trove"** for drug discovery. Plant-derived compounds often work through multiple targets and multiple pathways simultaneously, which may make them more versatile than conventional single-target drugs.

Traditional Chinese Medicine (TCM) has gained growing international attention in comprehensive cancer therapy due to its multi-target regulatory properties, low toxicity, and favorable clinical tolerability. There are already successful examples of plant-derived cancer drugs. **Paclitaxel**, extracted from the bark of the Pacific yew tree (*Taxus brevifolia*), is a core drug in combination chemotherapy for breast cancer, ovarian cancer, and non-small cell lung cancer. **Berberine**, an alkaloid from the TCM herb *Coptis chinensis*, was shown in a randomized controlled trial to prevent the recurrence of colon adenomas (precancerous polyps). These examples illustrate the broad potential of plant-based therapies.

## What Is Astragaloside-IV (AS-IV)?

*Astragalus membranaceus*, known as **Huangqi** in Chinese medicine, is a classic TCM herb with a history spanning thousands of years. It was first documented as a superior "Qi-tonifying" herb in the *Shennong Bencao Jing* (Divine Farmer's Classic of Materia Medica). Its immune-modulating effects, epitomized by the principle of **"strengthening vital Qi and stabilizing constitutional integrity,"** have been extensively validated by modern pharmacology.

The herb is rich in bioactive constituents such as saponins, flavonoids, and polysaccharides. Among these, **Astragaloside-IV (AS-IV)** is particularly notable. It belongs to a class of molecules called **lanostane-type tetracyclic triterpenoid saponins** and was first isolated and structurally characterized from Astragalus roots by Kitagawa and colleagues in **1983**.

Today, AS-IV is recognized as the **official quality marker for Astragalus** in the Chinese Pharmacopoeia. Its chemical designation is 3-O-β-D-xylopyranosyl-6-O-β-D-glucopyranosyl-cycloastragenol, with the chemical formula **C₄₁H₆₈O₁₄**.

AS-IV is not only the principal bioactive compound responsible for Astragalus's pharmacological effects, but it also demonstrates remarkable therapeutic efficacy in several areas, including cardiovascular protection, liver and kidney preservation, mitigation of diabetic complications, and anti-tumor activity. In oncology research, growing evidence highlights AS-IV's potent inhibitory effects across multiple cancer types, with recent studies revealing strong anti-HCC activity mediated through diverse molecular mechanisms.

## Study Methods: How This Systematic Review Was Conducted

This systematic review was conducted according to two rigorous international standards: the **PRISMA 2020 guidelines** (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and the **Cochrane Handbook for Systematic Reviews of Interventions**. Two independent researchers (XG and WH) performed comprehensive literature searches across **five authoritative databases**: PubMed, Cochrane, EMBASE, the China National Knowledge Infrastructure (CNKI), and Wanfang Data.

The search covered studies published from each database's inception through **March 2025**. Keywords included "astragaloside IV" and "hepatocellular carcinoma," along with related terms such as "astraloside," "ASIV," "astragalus," "astragaloside," "AS," "Huangqi," "hepatoma," "hepatic neoplasm," and "liver cancer." The researchers also manually reviewed reference lists of relevant literature to ensure no eligible articles were missed.

The inclusion criteria were highly specific:

1. The experimental drug had to be AS-IV alone, with the experimental group treated solely with AS-IV
1. The control group could not receive any other pharmacological interventions
1. The experimental subjects had to be either hepatocellular carcinoma cells or animals diagnosed with HCC through appropriate modeling techniques

Studies were excluded if they were reviews, abstracts, reports, or letters; if they contained incomplete or duplicate data; or if the experimental group received AS-IV combined with other drugs. Two researchers independently extracted data on authors, cell types, animal species, drug dosage, drug exposure time, and the molecular mechanisms of AS-IV in treating HCC. Any disagreements were resolved through discussion until consensus was reached.

## Key Findings: The 16 Studies at a Glance

The database search retrieved **172 potentially relevant articles**, and an additional **9 reports** were identified through manual searching. After removing **36 duplicate papers**, **145 papers** underwent screening based on titles and abstracts. Of these, **110 were deemed irrelevant**, leaving **35 papers** for full-text reading. Ultimately, **19 records were excluded**, and **16 articles** met all eligibility criteria and were included in the final analysis.

Among the 16 included studies:

-
**1 study** conducted only in vivo (animal) experiments
-
**8 studies** focused solely on in vitro (cell) experiments
-
**7 studies** employed both in vivo and in vitro approaches

In total, this provided **15 in vitro experiments** and **8 in vivo experiments** for analysis. The studies tested AS-IV on multiple liver cancer cell lines — including MeCC97-e, HepG2, Huh-7, SMMC-7721, Bel-7402, SK-Hep1, Hep3B, H22, SNU-182, and HSC-T6 — and in several animal models, including BALB/c mice with orthotopic (implanted in the liver) or subcutaneous tumors, and C57BL/6J mice with chemically induced HCC using DEN/CCl₄.

Doses ranged from **0.4 μM to 204 μM** in cell studies and from **20 to 150 mg/kg** in animal studies, with exposure times ranging from **4 hours to 140 days**. The researchers organized the findings into six major therapeutic mechanisms.

## Mechanism 1: Inhibiting Cancer Cell Growth (Proliferation)

Rapid, uncontrolled proliferation is a hallmark of malignant tumors and a key driver of cancer progression. Blocking this growth can slow or stop tumor progression and improve patient outcomes. **Almost all of the reviewed studies demonstrated that AS-IV significantly inhibits the proliferation of HCC cells.**

Many studies found that even low concentrations of AS-IV inhibit HCC cells, with a clear **dose- and time-dependent relationship**. Specific findings include:

-
**Xiaocui An's study** (HepG2 cells; 2.5, 5, and 10 μM): AS-IV inhibited HCC cell proliferation by modulating the NF-κB signaling pathway and regulating oxidative stress
-
**Three studies** (Lili Li; Chong Zhang; Fanggong Yong) showed AS-IV inhibits HCC proliferation through the Nrf2-mediated TGF-β/Smad3 pathway, while also suppressing intracellular reactive oxygen species levels and regulating different phosphorylation forms of Smad3
-
**Yuanzhang Zhu's study** (SNU-182 and Huh7 cells; 25 μM for 12 hours): AS-IV inhibited HCC cell proliferation and glycolysis by regulating KAT2A-mediated succinylation of PGAM1, a type of post-translational modification that occurs predominantly within mitochondria and plays a critical regulatory role in tumor development
-
**Chunmin Su's study** (SK-Hep1 and Hep3B cells; 100 and 200 μM for 1–2 days): AS-IV reduced the expression of anti-apoptotic proteins in HCC cells, thereby inhibiting proliferation

It is worth noting that one study — by Pengfei Ma and colleagues — found that treatment with 5–100 μg/mL AS-IV for 24, 48, and 72 hours had **no significant effect on the viability of MeCC97-e cells**. The researchers suggested this may be due to the low concentrations used, highlighting that dose optimization is critical for AS-IV's effectiveness.

## Mechanism 2: Blocking Cancer Spread (Metastasis and Invasion)

Metastasis and invasion are critical factors that allow tumors to spread throughout the body and lead to poor prognosis. A process called **epithelial-mesenchymal transition (EMT)** — in which cancer cells change their characteristics to become more mobile and invasive — is closely linked to cancer progression and spread.

Three studies in the review demonstrated that AS-IV interferes with this process:

-
**Yaling Li's study** (SMMC-7721 and Huh-7 cells; 204 μM for 2 days): AS-IV significantly down-regulated the expression of **lncRNA-ATB** (a long non-coding RNA associated with cancer spread) in a dose- and time-dependent manner, inactivating the IL-11/STAT3 signaling pathway. This induced apoptosis, reduced HCC cell viability, and inhibited metastasis and invasion
-
**Chengdong Qin's study** (Huh-7 cells; 15, 64, and 127 μM for 3 days): AS-IV treatment reduced the expression of EMT-related molecules by targeting the **Akt/GSK-3β/β-catenin pathway**, thereby weakening the invasive and migratory capabilities of HCC cells, with a clear dose-dependent relationship
-
**Ting He's study** (HepG2 cells; 25, 50, and 100 μM for 2 days): AS-IV at various concentrations inhibited EMT and suppressed metastasis and invasion by reducing the expression levels of **N-cadherin and vimentin** — two proteins that help cancer cells move — also showing a significant dose-dependent effect

## Mechanism 3: Triggering Cancer Cell Death (Apoptosis)

Apoptosis is the body's natural process of programmed cell death. It is an active, built-in mechanism that normally removes damaged or abnormal cells. In cancer, this process is often disabled, allowing malignant cells to survive and accumulate. Many cancer therapies work by reactivating apoptosis, and the review found that AS-IV does exactly this in HCC cells through several distinct routes:

-
**Xiaocui An's study**: AS-IV promoted apoptosis in HCC cells by modulating oxidative stress and the NF-κB signaling pathway, with a concentration-dependent effect
-
**Chunmin Su's study** (100 and 200 μM): AS-IV exhibited cytotoxic effects and triggered both exogenous (external) and endogenous (internal) apoptotic pathways, causing **G(1)-phase cell cycle arrest** and reducing the expression of anti-apoptotic proteins, thereby facilitating programmed cell death
-
**Ting He's study** (25, 50, 100 μM): AS-IV enhanced the expression of **Caspase-3 and Caspase-9** — key "executioner" enzymes in the apoptosis pathway — promoting cancer cell death and inhibiting HCC progression, in part through the Wnt/β-catenin pathway
-
**Xiang Cui's study** (SMMC-7721 and Huh7 cells; 25 μM for 1 day; plus in vivo studies): AS-IV induced the upregulation of **miR-150-5p** both in vitro and in vivo, which suppressed β-catenin (a protein that promotes cell survival and growth) and increased the apoptosis rate of HCC cells

## Mechanism 4: Strengthening the Immune System (Immunomodulation)

Immunotherapy has become one of the most exciting areas of cancer research in recent years. A key player in this field is **PD-L1 (programmed death ligand 1)**, a protein found on the surface of many cancer cells. When PD-L1 binds to its partner **PD-1 (programmed death-1)** on immune cells, it effectively acts like a "brake pedal," telling the immune system to stand down and not attack the tumor. This is one of the main ways cancers evade immune destruction.

The review found that AS-IV can interfere with this immune-evasion strategy in two important ways:

-
**Yang Ma's study** (Huh-7 and SMMC-7721 cells; 102 μM for 4 hours; in vivo at 50, 100, and 150 mg/kg for 40 days): AS-IV reduced PD-L1 levels on the cell surface through the **miR-135b-5p/CNDP1 axis**, alleviating PD-L1-related immunosuppression and thereby inhibiting HCC progression. This is significant because it suggests AS-IV could potentially work alongside modern immune checkpoint inhibitor drugs.
-
**Liang Min's study** (Huh-7 cells; 120 μM; in vivo at 20, 40, and 80 mg/kg for 40 days): AS-IV suppressed HCC by inhibiting the **M2 polarization of macrophages**. Macrophages are immune cells that normally help fight infection, but tumors can "hijack" them into an M2 state that actually promotes tumor growth. AS-IV blocked this hijacking through the TLR4/NF-κB/STAT3 signaling pathway, significantly reducing tumor volume and body weight in mice.

## Mechanism 5: Reversing Drug Resistance and Enhancing Chemotherapy

One of the biggest challenges in cancer treatment is drug resistance. Patients who undergo prolonged chemotherapy often develop tumors that no longer respond to treatment, leading to chemotherapy failure and cancer recurrence. Two studies in the review showed that AS-IV can help overcome this problem:

-
**Peipei Wang's study** (Bel-7402 cells, a drug-resistant HCC line; 100 μM for 1 day): AS-IV reversed drug resistance by down-regulating **MDR1** (multidrug resistance protein 1), a protein that acts like a "pump" in the cancer cell membrane, actively ejecting chemotherapy drugs before they can do their job. AS-IV achieved this by inhibiting the JNK/c-Jun/AP-1 signaling pathway.
-
**Xiaoyu Qu's study** (HepG2 and H22 cells; 0.4, 4, and 40 μM for 1 day; in vivo at 50 mg/kg for 14 days): AS-IV enhanced sensitivity to the chemotherapy drug **cisplatin** by suppressing **MRP2** (multidrug resistance-associated protein 2),

## Frequently Asked Questions

### What is astragaloside-IV and where does it come from?

Astragaloside-IV is a compound extracted from Astragalus membranaceus, also known as Huangqi, a traditional Chinese herb used for thousands of years. It is a type of saponin and is recognized as the official quality marker for Astragalus in the Chinese Pharmacopoeia. Researchers are studying its anti-cancer effects.

### How was this review of astragaloside-IV for liver cancer conducted?

The systematic review followed PRISMA 2020 and Cochrane guidelines. Two independent researchers searched five databases for studies published up to March 2025. They included 16 studies where astragaloside-IV was given alone to liver cancer cells or animals with liver cancer. Studies using astragaloside-IV combined with other drugs were excluded.

### What does astragaloside-IV do to liver cancer cells according to the review?

Animal and cell studies show astragaloside-IV acts through six mechanisms: it slows cancer cell growth, blocks spread, triggers cell death, strengthens immune defenses, reverses drug resistance, and cuts off the tumor's blood supply. However, these findings come from laboratory and animal studies, not human clinical trials.

### Is astragaloside-IV currently recommended for treating liver cancer in patients?

No. The researchers emphasize that large, well-designed human clinical trials are still needed before astragaloside-IV can be recommended as a mainstream liver cancer treatment. Current evidence comes from 16 laboratory and animal studies reviewed in 2025. Patients should consult their doctors for appropriate treatment options.

### Can astragaloside-IV help make chemotherapy more effective?

In two laboratory studies, astragaloside-IV helped overcome drug resistance in liver cancer cells. One study found it reversed drug resistance by reducing a protein that pumps chemotherapy drugs out of cells. Another showed it increased sensitivity to the chemotherapy drug cisplatin in cells and mice. Human trials are needed.

### Does astragaloside-IV affect the immune system's ability to fight liver cancer?

In cell and animal studies, astragaloside-IV reduced PD-L1 levels on liver cancer cells, which may lessen immune suppression. Another animal study found it blocked a process by which tumors hijack immune cells to promote growth. These immune-related effects have not yet been confirmed in patients.

### I have hepatocellular carcinoma and am thinking about astragaloside-IV (AS-IV) therapy. When should I seek a second opinion?

Astragaloside-IV (AS-IV), a compound from the herb Astragalus, has been shown in laboratory and animal studies to fight hepatocellular carcinoma through several mechanisms. However, researchers emphasize that large, well-designed human clinical trials are still needed before AS-IV can be recommended as a mainstream liver cancer treatment. If a patient is considering AS-IV or other traditional Chinese medicine options, a second opinion can clarify whether such approaches fit safely alongside established therapies. Diagnostic Detectives Network provides independent expert second opinions.


---
Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay.
Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact
Canonical page: https://diagnosticdetectives.com/products/how-a-compound-from-traditional-chinese-medicine-fights-liver-cancer-understanding-astragaloside-iv-as-iv-therapy-for-hepatocellular-carcinoma