Ziziphus spina-christi leaf extract in schistosomal liver disease: Biomarker gains in hepatectomy model-perioperatively actionable?

Abstract

Schistosomiasis is a major neglected tropical disease that leads to periportal fibrosis, portal hypertension, and compromised hepatic reserve. In endemic regions, the disease persists despite anthelmintic therapy, thereby increasing surgical risks. This editorial discusses the study by Alghamdi published in the World Journal of Hepatology, which evaluates the effects of Ziziphus spina-christi leaf extract (ZSCLE) in a hamster model of Schistosoma mansoni-induced fibrosis undergoing 50% partial hepatectomy. The study demonstrated that ZSCLE reduced hepatic egg burden, improved biochemical markers and inflammatory markers, activated cellular injury responses, and increased regeneration indices. Although these preclinical findings indicate potential benefits, they do not yet establish clinical perioperative efficacy due to the absence of definitive outcomes, such as post-hepatectomy liver failure, bleeding/transfusion surrogates, survival, and dynamic reserve testing. The central clinical question remains whether ZSCLE enhances hepatic tolerance and recovery following major surgical stress, possibly through anti-inflammatory/antioxidant signaling or direct antiparasitic activity, beyond improvements in biochemical markers alone. Future development of ethnomedicines should prioritize standardized research methodologies, comprehensive safety evaluations, and investigations incorporating clinically relevant functional endpoints and hard clinical outcomes to ensure both efficacy and safety in clinical settings.

Key Words: Schistosomiasis; Liver fibrosis; Hepatobiliary surgery; Ziziphus spina-christi leaf extract; Perioperative risk

Core Tip: This editorial examines a hamster model of Schistosoma mansoni-induced fibrosis, in which Ziziphus spina-christi leaf extract reduced egg burden and improved inflammatory markers. Although these preclinical findings are insufficient to establish clinical significance, they highlight key areas for future research, including standardizing interventions, conducting comprehensive safety profiling, and adopting rigorous study designs.

This editorial refers to "Enhanced surgical tolerance of schistosomiasis-induced fibrotic liver following treatment with Ziziphus plant extract" by Alghamdi, 2026; https://dx.doi.org/10.4254/wjh.v18.i1.114542.

---

INTRODUCTION

Schistosomiasis remains one of the most prevalent parasitic diseases globally, continuing to cause disproportionate morbidity in tropical and subtropical regions with limited healthcare infrastructure[1,2]. Schistosoma mansoni, a leading cause of intestinal schistosomiasis, is endemic across extensive regions of Africa, the Eastern Mediterranean, the Caribbean, and South America, where rivers, lakes, reservoirs, and irrigation canals sustain ongoing transmission[3]. Global estimates commonly report over 200 million active infections, with tens of millions affected by clinically significant disease[4].

For hepatologists and hepatobiliary surgeons, schistosomiasis-related liver disease is clinically characterized by periportal fibrosis, portal hypertension-primarily presinusoidal, resulting from increased resistance to portal flow at the level of portal tracts and portal venules upstream of the hepatic sinusoids-and associated presinusoidal vascular remodeling. Granulomatous inflammation surrounding the portal tracts, followed by concentric “pipe-stem” fibrosis, progressively distorts hepatic architecture and increases intrahepatic portal venous resistance[5]. As a result, patients may present with variceal bleeding, ascites, and hypersplenism, despite exhibiting a predominantly non-cirrhotic phenotype, while hepatic reserve and microcirculatory adaptability remain limited. When surgical intervention is indicated-such as resection for hepatocellular carcinoma, management of portal hypertension-related complications, or biliary procedures-the schistosomal fibrotic liver presents a high-risk operative substrate. Although praziquantel-based eradication and perioperative optimization are essential, established fibrosis and persistent hemodynamic fragility frequently limit the margin of safety for major surgical procedures[6].

In many endemic regions, traditional medicine is deeply embedded in health-seeking behavior. Plant-based preparations are commonly used to manage chronic illnesses and liver-related conditions. Ziziphus spina-christi (Christ’s thorn jujube) is widely regarded as a “liver-protective” tonic, and phytochemical analyses have identified flavonoids, saponins, tannins, and related compounds with reported antioxidant and anti-inflammatory properties[7]. Nevertheless, high-quality evidence from perioperative or surgery-relevant models remains limited. However, researchers have primarily focused on baseline hepatoprotective effects, with a significant knowledge gap in perioperative studies for schistosomal liver disease, particularly regarding hepatic tolerance and regeneration under resection stress. Additionally, key postoperative indicators, such as liver remnant function, portal inflow dynamics, and regeneration kinetics, remain underexplored, leaving clinical decisions without adequate theoretical and data support.

A recent experimental study published in the World Journal of Hepatology by Alghamdi[8], using a golden hamster model of Schistosoma mansoni-induced liver fibrosis, provides preliminary insight into this translational gap by evaluating whether Ziziphus spina-christi leaf extract (ZSCLE) is associated with more favorable regeneration-related outcomes following partial hepatectomy, thereby establishing a foundation for future clinical research[9].

FROM ETHNOMEDICINE TO PRECLINICAL RATIONALE

Ethnomedicine constitutes a substantial repository of empirical practice. However, translational progress requires converting traditional remedies into standardized products with reproducible composition, defined quality control measures, and clinically relevant endpoints. Ziziphus spina-christi serves as an illustrative example, as its longstanding reputation as a hepatic tonic corresponds with a plausible pharmacological basis[7].

Leaf extracts contain a variety of compound classes, including flavonoids (e.g., rutin- and quercetin-related compounds), polyphenols, triterpenoid saponins, tannins, and phytosterols[10,11]. These constituents have demonstrated antioxidative and anti-inflammatory properties, as well as the ability to modulate fibrotic signaling in multiple preclinical models. While these findings support potential pharmacological mechanisms, the predominant pathway by which these compounds exert effects in the schistosomiasis-hepatectomy model has not yet been clearly established[12-14].

In schistosomiasis, previous preclinical studies suggest that Ziziphus spina-christi preparations can attenuate granulomatous inflammation, reduce oxidative injury, and modulate profibrotic mediators[7]. By reframing the primary endpoint, the present study builds upon prior evidence: Rather than focusing solely on fibrosis attenuation, it investigates whether ZSCLE can enhance hepatic tolerance and post-resection recovery in a schistosomiasis-hepatectomy model, thereby supporting its translational potential.

This reframing is particularly relevant for clinical translation. The critical consideration is whether an intervention improves hepatic tolerance and recovery following major surgical stressors-such as bleeding, ischemia-reperfusion, vascular inflow control, and parenchymal transection-and supports regeneration, rather than merely improving baseline biochemical markers. Although the longstanding use of ethnomedicinal preparations provides historical context, it should not be interpreted as evidence of perioperative safety. Surgical stress, altered pharmacokinetics, and polypharmacy can significantly modify risk profiles. Therefore, traditional remedies must undergo rigorous evaluation through standardized, well-designed studies before clinical application.

KEY FINDINGS IN A SURGICALLY RELEVANT MODEL

In a golden hamster model of Schistosoma mansoni-induced liver fibrosis subjected to a standardized 50% partial hepatectomy, ZSCLE demonstrated significant effects on liver function and regeneration. ZSCLE treatment resulted in an approximate 70% reduction in hepatic egg burden, indicating its potential to lower parasitic load within the liver. It also improved biochemical parameters, including liver enzyme levels and bilirubin, and reduced inflammatory markers such as tumor necrosis factor alpha and interferon gamma, suggesting attenuated hepatic injury and inflammation.

Moreover, ZSCLE markedly enhanced liver regeneration, with higher regeneration indices particularly evident in the ZSCLE plus hepatectomy group. The treatment also diminished cellular injury, as reflected by decreased DNA fragmentation, indicating a protective effect on hepatocytes. These findings suggest that ZSCLE may enhance hepatic tolerance and promote recovery following major surgical stressors such as hepatectomy, highlighting its potential as an adjunct to perioperative care in schistosomiasis-related liver disease. However, additional studies are required to assess its clinical applicability and safety in human populations.

However, additional studies are required to assess its clinical applicability and safety in human populations. However, it is important to note that the current results are primarily based on surrogate and biochemical markers and do not demonstrate a significant improvement in surgical tolerance. Therefore, further studies are needed to assess the clinical applicability and safety of ZSCLE in human populations, particularly in improving surgical tolerance and other clinical outcomes.

WHY THIS COULD MATTER: A PLAUSIBILITY FRAMEWORK

Schistosomiasis-related periportal fibrosis is a dynamic pathological process driven by multiple factors, including egg deposition, granulomatous inflammation, oxidative stress, hepatic stellate cell activation, and vascular remodeling[15]. Stressors associated with major surgery, such as hemodynamic fluctuations, systemic inflammation, tissue hypoxia, and ischemia-reperfusion injury, can further exacerbate liver dysfunction, particularly in patients with limited hepatic reserve.

The mechanism of action of ZSCLE is consistent with this pathophysiological framework. It reduces the parasitic burden, suppresses granulomatous inflammation, downregulates signaling pathways associated with inflammation and oxidative stress, and modulates the expression of markers of cellular injury and apoptosis.

It is important to emphasize that these markers serve as indicators of perioperative pathology rather than clinical endpoints. Nonetheless, ZSCLE appears to enhance the liver’s regenerative and reparative capacity. Notably, the conclusions of this study remain confined to the preclinical stage. As the investigation did not include key clinical endpoints-such as perioperative mortality, post-hepatectomy liver failure, or assessments of functional hepatic reserve-the translational relevance of the findings has yet to be established.

TRANSLATIONAL NEXT STEPS: CRITICAL ISSUES TO ADDRESS BEFORE HUMAN APPLICATION

Although ZSCLE has demonstrated promise in preclinical studies, several challenges must be resolved before clinical translation. Most notably, the study is based on a golden hamster model, which differs from humans in hepatic regenerative capacity, immune responses, and portal hemodynamics. Further validation is required to determine whether these findings can be reliably extrapolated to human physiology. Future studies should aim to more accurately replicate human clinical conditions, particularly in patients with schistosomiasis-related liver fibrosis.

Moreover, the study did not assess critical clinical endpoints, such as perioperative mortality or functional hepatic reserve, thereby limiting its relevance to clinical practice. Consequently, future research should focus on evaluating clinical outcomes, particularly hepatic recovery following surgical intervention. Future research should focus on evaluating clinical outcomes, particularly liver recovery following surgical intervention, using perioperative measures such as dynamic reserve testing (e.g., indocyanine green clearance, LiMAx if available), international normalized ratio, bilirubin, lactate trajectories, and portal pressure/flow.

Although improvements in biochemical markers were reported, these changes do not necessarily translate into clinical benefit[16]. Further investigations are required to determine whether ZSCLE confers meaningful perioperative advantages, especially with respect to hepatic tolerance and recovery after major surgical stress. Clinical endpoints, including post-hepatectomy liver failure and liver function restoration, should be prioritized in subsequent studies. Future research should prioritize clinical endpoints, including post-hepatectomy liver failure, liver function recovery, and survival.

Furthermore, the precise mechanisms underlying ZSCLE’s antiparasitic and hepatoprotective effects remain to be fully elucidated. From a translational standpoint, ZSCLE also faces several challenges as a potential therapeutic agent. It must be developed as a standardized product with clearly defined sourcing, extraction procedures, and contamination control measures. The dose-response relationship has not yet been established, necessitating further research to determine the optimal dosing regimen. In addition, because perioperative patients frequently receive multiple medications, the potential for herb-drug interactions must be thoroughly investigated to ensure safety in clinical use.

In summary, successful clinical translation of ZSCLE requires addressing several key issues, including experimental design, the incorporation of clinically meaningful endpoints, standardization of the extract, dose optimization, and comprehensive safety evaluation. If these challenges are resolved, ZSCLE may emerge as a potential adjunct therapy for perioperative liver protection, particularly in patients with schistosomiasis-associated liver fibrosis.

CONCLUSION

Schistosomiasis-related periportal fibrosis and portal hypertension remain significant challenges to safe hepatobiliary surgery in endemic regions. Although anthelmintic therapy and perioperative optimization are essential, they often fall short in restoring hepatic reserve or microcirculatory resilience. The preclinical study discussed herein offers encouraging findings from a controlled golden hamster model: ZSCLE reduced hepatic egg burden, improved biochemical and inflammatory markers, and enhanced regeneration indices following a standardized 50% partial hepatectomy. However, these results are preliminary and do not establish perioperative efficacy or surgical safety in humans.

Rather than positioning Ziziphus spina-christi as an immediate perioperative adjunct, these findings highlight the necessity of a structured translational pathway. Rigorous standardization, well-designed dose-response studies, toxicological evaluations under surgical stress conditions, and comprehensive assessments of herb-drug interactions are essential prerequisites for clinical application. Historical ethnomedicinal use, while informative, cannot substitute for systematic safety evaluation in surgical contexts-particularly in settings involving polypharmacy. If these critical criteria are met, ZSCLE may ultimately serve as an adjunctive strategy for perioperative liver protection in resource-limited, schistosomiasis-endemic regions. In summary, ZSCLE is a hypothesis-generating adjunct candidate, contingent on functional endpoints and perioperative safety pharmacology. It should be positioned as complementary-not substitutive-to praziquantel eradication and modern perioperative optimization. Future development requires multidisciplinary collaboration, integrating hepatobiliary surgery, parasitology, pharmacognosy, and regulatory science, to ensure evidence-based advancement.