New Study: Modified Citrus Pectin Protects Liver and Lungs
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Methotrexate (MTX) is a cornerstone drug in the treatment of cancer, autoimmune diseases, and inflammatory disorders, but its therapeutic benefits come at a steep cost—serious toxicity to the liver and lungs. For patients relying on MTX to manage cancer, side effects such as organ damage can become a double-edged sword, forcing difficult decisions between effective treatment and long-term organ health. Despite decades of clinical use, strategies to protect vulnerable tissues from MTX-induced injury remain limited, highlighting an urgent need for safe, adjunctive therapies.
This is where natural compounds like modified citrus pectin (MCP) are gaining scientific attention as modulators of inflammatory and fibrotic pathways. A new study explores whether MCP can mitigate MTX toxicity at a molecular level, further substantiating MCP’s novel, dual-purpose approach: preserving and enhancing the therapeutic power of conventional cancer approaches, while safeguarding organs and tissues to support greater clinical outcomes.
The new study, "Modified citrus pectin ameliorates methotrexate-induced hepatic and pulmonary toxicity: role of Nrf2, galectin-3/TLR-4/NF-κB/TNF-α and TGF-β signaling pathways" investigates the protective effects of modified citrus pectin (MCP) against methotrexate (MTX)-induced toxicity in hepatic and pulmonary tissues, focusing on specific molecular signaling pathways.1
Background: Methotrexate, a widely used chemotherapeutic and immunosuppressive agent, is associated with significant hepatotoxicity and pulmonary toxicity. The pathogenesis of MTX-induced toxicity involves oxidative stress, inflammation, and fibrosis. Galectin-3, a β-galactoside-binding lectin, has been implicated in various fibrotic and inflammatory conditions. Modified citrus pectin, a derivative of pectin rich in galactose residues, can bind galectin-3, potentially modulating its activity. This study explores MCP's potential to mitigate MTX-induced organ toxicity by modulating oxidative stress, inflammatory responses, and fibrotic processes.
Methods: Male Wistar rats were allocated into four groups: a control group receiving saline, an MCP group receiving MCP (400 mg/kg/day) orally for 11 days, an MTX group receiving a single intraperitoneal dose of MTX (20 mg/kg) on the 7th day, and a combined MTX + MCP group receiving both treatments as described. On the 11th day, animals were euthanized, and liver and lung tissues were harvested for biochemical assays, histopathological examination, and molecular analyses.
Biochemical Assessments: Serum levels of hepatic enzymes—alanine aminotransferase (ALT) and aspartate aminotransferase (AST)—were measured to assess liver function. Markers of oxidative stress, including malondialdehyde (MDA) levels and activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), were quantified in liver and lung tissues.
Histopathological and Immunohistochemical Analyses: Tissue sections were stained with hematoxylin and eosin (H&E) for general morphology and Masson's trichrome for fibrosis assessment. Immunohistochemical staining was performed to detect the expression of galectin-3, nuclear factor erythroid 2–related factor 2 (Nrf2), and transforming growth factor-beta (TGF-β).
Molecular Analyses: Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were utilized to evaluate the expression levels of key signaling molecules, including Toll-like receptor 4 (TLR-4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-alpha (TNF-α), and TGF-β.
Results:
- MTX administration resulted in elevated serum ALT and AST levels, indicating hepatic injury. Co-treatment with MCP significantly reduced these enzyme levels compared to the MTX group. MTX increased MDA levels and decreased SOD and CAT activities in both liver and lung tissues, suggesting enhanced oxidative stress. MCP co-administration mitigated these effects, restoring antioxidant enzyme activities and reducing lipid peroxidation.
- MTX-treated rats exhibited marked hepatic and pulmonary structural damage, including inflammatory infiltrates and fibrosis. MCP co-treatment ameliorated these histopathological alterations, preserving tissue architecture and reducing fibrosis.
- MTX exposure upregulated galectin-3, TLR-4, NF-κB, TNF-α, and TGF-β expression while downregulating Nrf2 in liver and lung tissues. MCP co-treatment reversed these changes, decreasing pro-inflammatory and pro-fibrotic markers and enhancing Nrf2 expression.
This study demonstrates that modified citrus pectin (MCP) exerts protective effects against methotrexate (MTX)-induced hepatic and pulmonary toxicity, with clear mechanistic insights involving the modulation of oxidative stress, inflammatory signaling, and fibrotic pathways.
Specifically, MCP mitigates MTX-induced organ damage by enhancing Nrf2-mediated antioxidant defense, inhibiting galectin-3/TLR-4/NF-κB/TNF-α-driven inflammatory cascades, and suppressing TGF-β-associated fibrotic responses in liver and lung tissues.
While previous studies have reported general anti-inflammatory and anti-fibrotic properties of MCP—primarily in the context of cancer metastasis, fibrosis, and cardiovascular diseases—this study is among the first to comprehensively elucidate the molecular mechanisms by which MCP protects against chemotherapeutic organ toxicity in both hepatic and pulmonary systems.
These findings underscore MCP’s potential as an adjunctive therapeutic agent in patients receiving methotrexate, particularly for those at risk of hepatic and pulmonary complications, thus expanding MCP’s clinical relevance as an effective adjunct in oncology protocols. As research into MCP continues to gain momentum in the independent literature, it is increasingly clear that this botanically-derived agent is a promising candidate for further research into natural compounds targeting complex, multi-organ toxicities associated with chemotherapeutic agents.
Source:
Ismail R, et al. Modified citrus pectin ameliorates methotrexate-induced hepatic and pulmonary toxicity: role of Nrf2, galectin-3/TLR-4/NF-κB/TNF-α and TGF-β signaling pathways. Front Pharmacol. 2025;16:1528978. doi:10.3389/fphar.2025.1528978.