Ruangan Granule (RG)

What It Is

Ruangan Granule (RG) is a traditional Chinese medicine (TCM) herbal formula (a compound herbal preparation) used particularly in China for liver-related diseases, especially liver fibrosis and early cirrhosis.

In some contexts, RG is combined with or compared to “Biejia Ruangan” formulations or “softening the liver” (in Chinese, “软肝颗粒”) preparations. ScienceDirect

The formula typically consists of several herbal components (and sometimes animal-derived components in classical TCM formulations). For instance, one published study lists eight raw materials:

• Carapax of Trionyx sinensis (Biejia)
• Roots of Paeonia lactiflora (Chishao)
• Astragalus membranaceus (Huangqi)
• Atractylodes macrocephala (Baizhu)
• Angelica sinensis (Danggui)
• Salvia miltiorrhiza (Danshen)
• Senna tora (Juemingzi)
• Prunella vulgaris (Xiakucao) Frontiers

More recently, a developed version called Huangjia Ruangan Granules (HJRG) is being studied in clinical trials (e.g. phase III for chronic hepatitis B–related fibrosis) as a more standardized medicinal product. Synapse

So, RG is not a single isolated chemical, but a multi-component herbal (and partly TCM animal/herbal hybrid) preparation intended to act via multiple pathways in the liver.

How It Works (Mechanisms of Action, Proposed and Observed)

Because RG is a complex herbal mixture, its “mechanism” is multifactorial, and many of the mechanistic insights come from animal, cell, or network pharmacology studies rather than definitive human mechanistic trials. Here’s what is known or hypothesized:

Anti-fibrotic effects / inhibition of collagen deposition

• In rat models (e.g. carbon tetrachloride, CCl₄–induced liver fibrosis), RG treatment has been shown to reduce collagen fiber proliferation in hepatic tissue (as seen by Masson staining) and reduce expression of fibrosis markers such as collagen I, α-SMA (alpha smooth muscle actin) in liver tissue. ChinJMap
• RG also downregulates transcriptional and protein expression levels of fibrotic pathway mediators (e.g. RhoA, ROCK1) in these models, suggesting suppression of the RhoA/ROCK signaling pathway. ChinJMap
• In another study, RG was shown to inhibit activation of the PI3K-Akt signaling pathway in fibrotic liver models, which is believed to play a role in hepatic stellate cell (HSC) activation and fibrogenesis. Frontiers

Anti-inflammatory and oxidative stress modulation

• RG (or in particular formulations such as HJRG) has been shown to reduce inflammatory cytokines (e.g. TNF-α, IL-1β, IL-6), inhibit activation of NF-κB signaling, and suppress phosphorylation in MAPK pathways (ERK, JNK, p38) in rat models of liver injury. Synapse
• RG treatment can help raise levels of antioxidant markers (e.g. superoxide dismutase (SOD), glutathione) and reduce markers of oxidative stress (e.g. malondialdehyde (MDA), myeloperoxidase). Synapse
• In one rat liver fibrosis/inflammation model, HJRG reversed increased expression of TNFR1 (tumor necrosis factor receptor 1) and suppressed the TNF/MAPK and NF-κB pathways. Wiley Online Library

Synergy with conventional antiviral therapy

• In a multicenter, randomized clinical trial, RG combined with entecavir (ETV), an antiviral used in chronic hepatitis B (CHB), was more effective at regressing fibrosis/inflammation and improving histopathology outcomes compared to ETV alone. X-MOL
• The combined therapy had higher rates of fibrosis regression (defined by certain pathologic score reductions) and better improvements in imaging/serologic fibrosis indices, as well as a lower long-term risk of hepatocellular carcinoma (HCC). X-MOL

Regulation of metabolism / systems biology perspective

• Using network pharmacology and metabolomics approaches (i.e. computational linking of compound-target networks plus metabolic profiling), studies have suggested that RG’s active compounds (such as ferulic acid, salvianolic acid B, paeoniflorin, luteolin, quercetin, kaempferol) may act on multiple pathways (oxidative stress, inflammation, mitochondrial function, pyrimidine metabolism) to counter liver fibrosis. Frontiers
• These “multi-target, multi-component” approaches are typical of how TCM formulas are studied in modern pharmacology. Frontiers

In summary: RG is thought to act by inhibiting fibrotic signaling, reducing inflammation and oxidative stress, and synergizing with antiviral therapies, among other effects.

Why It’s Important (Clinical & Research Significance)

Addressing unmet need in liver fibrosis therapy

• Liver fibrosis (and progression to cirrhosis) is a major global health issue, especially in patients with chronic hepatitis B or other chronic liver insults. Currently, there are limited effective pharmacological therapies that can reliably reverse fibrosis. RG offers a potential adjunctive or alternative approach. Frontiers

Potential to improve outcomes in chronic hepatitis B (CHB)

• In CHB, antiviral therapy (e.g. entecavir) is standard, but reversal of advanced fibrosis or early cirrhosis is often incomplete. The trial data suggest that RG may augment fibrosis regression and reduce the risk of HCC in these patients. X-MOL

Bridging Traditional and Modern Medicine

• RG is an example of how traditional herbal formulas are being standardized, studied in rigorous clinical trials, and developed into pharmaceutical products (e.g. HJRG in phase III). This helps bridge TCM practice with evidence-based medicine. Synapse

Potential for reduced HCC incidence

• Longitudinal follow-up in the RG + entecavir trial showed lower HCC incidence in that group compared to ETV alone. While this is promising, it is observational and needs more confirmation. X-MOL

Ongoing development and regulation

• RG / HJRG is in active development, with a randomized, double-blind, multicenter phase III clinical trial initiated to establish its safety and efficacy in treating liver fibrosis in the setting of CHB. Futu News

Thus RG is important clinically as a promising complementary therapy for liver fibrosis and scientifically as a model for integrating TCM formulations into evidence-based therapeutics.

Considerations (Cautions, Limitations, Open Questions)

When considering RG in a health/clinical context, there are several caveats, limitations, and points to watch:

Quality of evidence / limited large randomized trials

• Many mechanistic studies are in animals or cell culture; translation to humans is not guaranteed.
• The biggest clinical trial combining RG + ETV in CHB patients is promising, but further replication, longer follow-up, and independent trials are needed. X-MOL
• In older literature (e.g. one clinical observation from 2002), RG was compared with Biejia Ruangan tablet over 3 months in 120 patients, showing some improvements in fibrosis biomarkers, but methodological limitations exist in those older studies (sample size, blinding, long-term follow-up). SpringerLink

Standardization and variability

• As with many herbal formulas, batch variability, purity, source quality, and consistency of active ingredient concentrations are concerns.
• The newer HJRG formulation is intended to be a more standardized product, but its standardization and manufacturing controls must be validated. Synapse

Safety, toxicity, and side effects

• Animal studies used “safe doses” in experiments, but human safety data are more limited. Frontiers
• Because RG is multi-component, interactions with other medications (especially liver-metabolized drugs, antivirals, etc.) are possible but not fully characterized.
• Some herbs in RG (or related formulas) may exert effects on coagulation, blood circulation, or other systems; in patients with comorbidities (e.g. bleeding risk, renal disease) caution is warranted.
• The long-term safety in humans (especially in those with compromised liver function) needs careful monitoring.

Herbal-drug interactions / pharmacokinetic issues

• Potential interactions between RG’s herbal components and conventional drugs (e.g. antivirals, immunosuppressants, statins) are a real concern but underexplored.
• Effects on cytochrome P450 enzymes, transporters, or other metabolic pathways may alter drug levels.

Patient selection and TCM pattern differentiation

• In TCM practice, RG is not used universally; patients are often assessed by “syndrome differentiation” (e.g. “liver qi stagnation,” “spleen deficiency,” “blood stasis obstructing collaterals”) to decide whether RG is appropriate. Synapse
• It may be less effective in advanced cirrhosis or decompensated liver disease (beyond what trials have tested).

Regulatory and approval status

• RG / HJRG is not yet universally approved in all jurisdictions (e.g. outside China). Its status is still under regulatory review (e.g. phase III trials). Futu News
• Even in China, clinical implementation must comply with regulatory guidelines, pharmacovigilance, and standard-of-care constraints.

Cost, accessibility, and integration into standard care

• The cost, accessibility, and reimbursement for RG/ HJRG may limit widespread adoption, especially outside China.
• Integrating TCM formulas like RG into conventional hepatology practice requires education, clinical guidelines, and acceptance by hepatologists and regulatory bodies.