The rising global prevalence of non-communicable diseases (NCDs), and associated mortality and reduced quality and expectancy of life, poses one of the most pressing public health challenges of the 21st century (Hunter and Reddy, 2013; World Health Organization, 2014; World Health Organization, 2025). Modifiable and non-modifiable risk factors such as unhealthy diet, physical inactivity, globalization-induced lifestyle changes, aging, stress, metabolic abnormalities, tobacco and alcohol use, as well as genetic and environmental factors are fuelling the prevalence of NCDs (Cuevas Garciá-Dorado et al., 2019; Brauer et al., 2024; Formichi et al., 2025). Metabolic dysfunction-associated steatotic liver disease (MASLD), driven primarily by dysregulated glucose and lipid metabolism, is one such emerging global health issue (Feng et al., 2024; Scoditti et al., 2024). The multifactorial aetiology and systemic pathophysiology of MASLD often constrain the effectiveness of conventional molecular medicines, making an integrative medicine approach, effectively merging holistic and reductionist views of biology, relevant and imperative. This perspective article underscores the urgency of creating a transdisciplinary knowledge framework, bridging epistemologically and ontologically different medical systems, for an omniscient view of the MASLD disease biology; and examines its potential benefits, opportunities, and challenges in advancing MASLD management within the evolving landscape of NCDs.

The complex pathophysiology, asymptomatic early stages, lack of consensus on standard diagnostic protocols, absence of universally accepted pharmacological interventions, and strong association with multiple comorbidities make early diagnosis and effective management of MASLD a great challenge (Ma et al., 2025; Adinolfi et al., 2026). Although non-invasive and invasive diagnostic options like biomarkers, imaging techniques and liver biopsy exist, their limited accessibility, affordability and patient compliance restrict widespread use (Garg et al., 2025; Nowak et al., 2025). MASLD diagnosis is often incidental during routine health check-ups as most of the early-stage symptoms like mild fatigue, bloating and abdominal discomfort are non-specific and often overlooked. Sometimes even the advanced stages like fibrosis, cirrhosis and cancer remain with non-specific symptoms or asymptomatic making MASLD underdiagnosed until serious outcomes (cirrhosis or HCC) occur (Sharma and Arora, 2020; Mishra et al., 2022).

Management approaches for MASLD can be broadly categorized into preventive, therapeutic and surgical interventions. Although lifestyle and dietary modifications remain as the cornerstone of MASLD prevention, poor patient adherence often limits long-term benefits (Arora et al., 2021; Wang et al., 2023). For instance, while the Mediterranean diet is beneficial for MASLD management, its global adoption is limited due to cultural, geographic, seasonal, and socioeconomic differences (Tsofliou et al., 2022; Cueto-Galán et al., 2025). Similarly, aerobic exercise and resistance training for weight loss is limited by resources, supervision, and difficulty in sustaining significant weight loss (Willis et al., 2012; Mahmood et al., 2023).

The major challenge in therapeutics is the absence of FDA-approved drugs for MASLD or cirrhosis (Mallet et al., 2024; Drygalski and Drygalski, 2025). Resmetirom (a thyroid hormone receptor beta (THR-β) agonist), the first FDA-approved drug for MASH and Saroglitazor (a dual PPARα/γ agonist), approved in India for T2D and MASH treatment are promising drug options, but needs more data on sustained histological benefits and long-term safety (Chhabra et al., 2022; Chaudhuri et al., 2023; Harrison et al., 2024; Mir et al., 2024).

Other pharmacological targets like incretin hormone agonists (Semaglutide and Trizeptide), SGLT2 inhibitors, FGF-21 analogue, PPAR agonists, antioxidants, and anti-inflammatory agents are actively investigated for MASLD management, but none have demonstrated clinically significant improvement in liver outcomes across diverse patient populations (Musso et al., 2017; Francque et al., 2021; Loomba et al., 2023, 2024; Sanyal et al., 2025). Surgical approaches including Roux-en-Y gastric bypass and liver transplantation, forms the third strategy. Though bariatric surgery and endoscopic bariatric therapies are beneficial to some extent, patients with end stage cirrhosis are generally left with liver transplantation as the only solution and it is expensive and associated with higher rates of complications, malnutrition, sarcopenia, morbidity and mortality. They often require multi-speciality care including hepatologists, endocrinologists, cardiologists, and dietitians (Fakhry et al., 2019; Lassailly et al., 2020; Aminian et al., 2021). The perpetually growing prevalence and strong association with co-morbid conditions makes a one-size-fits-all approach irrelevant for MASLD diagnosis and management.

Are current clinical frameworks for MASLD overlooking something essential? Probably ‘YES’. Philosophically the epistemology and ontology of modern biomedicine is grounded in molecular reductionism emphasizing a lock-and-key model of disease mechanisms and drug discovery. While this approach has been highly effective in treating infectious diseases, its limitations in managing complex lifestyle disorders like MASLD are increasingly evident. Its non-linear dynamics, multisystem pathophysiology and the role of systemic metabolic dysfunction in the pathogenesis demands integration of molecular and systemic perspectives for early diagnosis, prevention, and therapy. Resonating with the global interest in complementary and alternative medicine (CAM), the MASLD management landscape calls for an integrative framework that incorporates holistic principles of disease biology from complementary systems (World health organization, 2023). Indian Systems of Medicine (ISMs) like Ayurveda and Traditional Chinese Medicine (TCM) are driving transformative progress in this direction. Of the two, Ayurveda stands out as the oldest codified medical system deeply rooted in the Indian philosophical axioms of logic, epistemology and metaphysics.

Ayurveda, a holistic system of medicine originating from the Indian subcontinent, offers a distinct epistemology and ontology for understanding the biological mechanisms underlying human health and disease. This unique worldview, however, presents challenges when attempting to integrate it with contemporary scientific discourse. The following section provides a brief overview of how Ayurveda understands the liver, its biological functions and the disease biology. A glossary is provided separately for readers to understand the unique Sanskrit terminologies used in Ayurveda.

In Ayurveda, the liver is referred to by the term Yakrit, a Sanskrit word meaning “to govern” (Apte, 1890). The description of Yakrit highlights its principal and crucial role in modulating “Agni” - the metabolic fire responsible for digestion, metabolism, and nutrient transformation (Sastry, 1997e). In Ayurveda parlance, after digestion, the food (Ahara) is transformed into an absorbable form referred to as “Ahara Rasa” which then transforms into “Rasa Dhatu,” the basic element of nourishment that circulates throughout the body (Sastry, 1997b; Murthy, 2001a). Upon reaching Yakrit (liver), Rasa Dhatu transforms into “Rakta Dhatu” (whole blood), producing “Pitta” (∼ bile juice) as a byproduct that get secreted into the gastro-intestinal tract (GIT) to support digestion, metabolism and nutrient transformation (Acharya, 1992a; Sastry, 1997f; Sastry, 1997d; Sastry, 1997a; Murthy, 2001b; Murthy, 2001c).

Although Ayurvedic narrative of liver biology does not map directly to the contemporary biological understanding of hepatology and the disease construct of MASLD, as a science that studies biological changes, Ayurveda offers a structured explanation of disease pathophysiology through a unique “six-stage disease progression model” referred to as Shad-Kriyakala (Chaple et al., 2016; Chauhan et al., 2017; Bishnoi et al., 2024). This framework centres around a few core concepts of Ayurveda, central to the biology of health and disease: Ama, Agni, Kapha and Pitta. Ama represents the accumulated ‘metabolic waste’ in the body arising from improper and incomplete nutrient metabolism. Agni refers to the digestive and metabolic functions responsible for preventing Ama accumulation (Sastry, 1997c; Naaz et al., 2025). Kapha and Pitta constitute two of the three fundamental biological forces (Dosha) that govern the physiological and biochemical homeostasis. Drawing from this model in Ayurveda, this article proposes an Ayurveda-Biology hypothesis of MASLD progression, with plausible correlation of Ayurvedic concepts of disease progression with molecular events (Figure 1). However, this correlation requires more detailed research for deeper scientific validation. Ayurveda posits that the MASLD progression begins when inappropriate diet and lifestyle - particularly those increasing Kapha and Pitta - impair Agni functions and lead to Ama accumulation (Sanchaya stage). Excess consumption of sweet, sour, savour, oily and heavy to digest foods are typically known to impair Dosha (Kaptha and Pitta) and Agni functions at GIT. The vitiated Dosha and accumulated Ama disrupts the dynamic equilibrium of physiological and biochemical functions in different parts of the body (Prakopa stage) (Asija and Singh, 2016; Saini and Lata, 2025). Eventually the absorbable form of food (Ahara Rasa) and nourishment (Rasa Dhatu) get vitiated, but circulate in the body and reach Yakrit, the liver (Prasara stage) (Acharya, 1992b; Murthy, 2001d). A simple analogy can illustrate this phenomenon: If the body is viewed as a house, each organ is a room with a defined function. When the accumulated waste in one room remains undisposed, it decomposes and eventually affects the entire house. At the liver, the pathophysiology is localized (Sthana Samshraya stage) causing liver steatosis, which in turn manifests with various clinical symptoms (Vyakti stage) and ends-up with complications (Bheda stage).

The key insight from this perspective is the foundational role of the gut in systemic health. An earlier work from Thottapillil and colleagues highlighted gut as a convergence point for an integrative Ayurveda-Biology framework of diabetes management; which holds true for MASLD as well (Thottapillil et al., 2021). Dietary quality and quantity, eating behaviour, seasonal and circadian rhythms, physical activity, and mental stress are key determinants of gut functions that influence nutrient transformation and metabolic balance. From an Ayurvedic perspective, impaired digestive–metabolic capacity (Agni-mandya) and accumulation of Ama create an internal milieu that can be conceptually aligned to inflammation and gut-microbiome dysbiosis resulting in compromised intestinal barrier function and ‘leaky-gut’ effect (Mishra et al., 2025; Shruti et al., 2025). This permits microbes, their products and other toxins to reach the liver, eventually triggering inflammation and oxidative stress culminating in MASLD and cirrhosis (Ray, 2015; Portincasa et al., 2021). Therefore, the emphasis Ayurveda gives for proper regulation of gut functions (Agni) to reduce Ama provides avenues for early-stage management of MASLD through diet, lifestyle modifications and therapeutic interventions (Feng et al., 2017; Fujisaka et al., 2024; Sharma, 2024).

The distinctive conceptualization of liver biology in Ayurveda and other traditional medical systems of South and South-East Asia provides a unique logic for systems-based therapeutics to restore the body’s metabolic homeostasis. These traditions extensively use medicinal plants by leveraging their phytochemical diversity, to create a rational blend of pharmacological properties that modulate interconnected metabolic pathways; thereby promoting adaptive and dynamic metabolic homeostasis. In Ayurveda, this pharmaceutical logic is systematically articulated through the concepts of Rasapanchaka of Dravyaguṇa (Joshi et al., 2007; Rath et al., 2014; Thakur et al., 2022). While this approach contrasts with reductionist pharmacology, it is increasingly supported by systems biology and network pharmacology; and is essential for managing diseases like MASLD that are arising from systemic dysregulation involving inter-organ communication (Chandran et al., 2017; Thottappillil et al., 2024). Supplementary Table 1 provides a curated list of medicinal plants illustrating how Ayurveda-informed phenotypic determinants translate into the selection of pharmacologically coherent, multi-target interventions relevant to MASLD.

The interconnected tapestry of etio-pathophysiology of MASLD, governed by biological, lifestyle, environmental and sociocultural factors, demands an approach that transcends any single therapeutic framework. The very foundation of trans-disciplinarity is rooted in the principles of complexity science and chaos theory - disciplines that reveal an interconnected yet non-linear nature of reality. Human health and disease exemplify non-linear dynamic systems that require the integration of multiple, and often epistemologically distinct, knowledge systems (Jayasinghe, 2012; Biswas et al., 2018). The limitations of traditional lock-and-key framework in addressing the interconnectedness of complex etiopathological determinants highlight the need for systems approach and precision medicine models (Priego-Parra et al., 2025). Within this context, Ayurveda, as a whole-system medical tradition grounded in principles aligned with P4 medicine, offers a space for developing novel integrative strategies for MASLD management. Creating a transdisciplinary framework that bridges Ayurveda and conventional biomedicine opens new avenues for early detection, prevention, and personalized interventions to restore and maintain the dynamic metabolic homeostasis (Figure 2). The primary goal of this framework should be to prevent disease onset and progression of MASLD while improving the individual and population level quality of life through personalized, culturally-sensitive, and evidence-based strategies.

The global trend of traditional medicine-based disease management, particularly noncommunicable diseases, highlighted in the WHO’s Traditional Medicine Global Summit report (2023) (World Health Organization, 2023) underscores the need of harnessing the holistic understanding of the disease pathophysiology of the TMs with the mainstream treatment protocols. The proposed framework for MASLD management, integrating systemic insights of Ayurveda with molecular precision of biomedicine, offers promising early and preventive interventions, culturally aligned and personalized care, and multi-targeted therapeutics. However, the heterogeneity of herbal products, regulatory divergence across jurisdictions, limited mechanistic understanding of multi-targeted therapeutics, and the need for clinician cross-training remain as challenges. Overcoming them through coordinated education, research, and policy initiatives can open up novel integrative, globally adaptive and patient-centred management strategies for MASLD.

For advancing the proposed transdisciplinary Ayurveda–Biology framework from a conceptual note to clinical implementation, the following priority areas warrant focused attention.

Standardization and Material Reproducibility: Rigorous phytochemical characterization and batch-to-batch standardization of Ayurvedic interventions using validated analytical platforms to ensure reproducibility, safety, and translational credibility.

Agni: The simple translation of Agni is ‘fire’. However, in Ayurveda, Agni is a phenomenon that can be understood as a fundamental ‘energy form’ and governing principle of the biotransformation of substances in the body. At a gross level of physiology, Agni encompasses all the functions regulating digestion and absorption of nutrients from ingested food. At cellular and tissue level, Agni denotes the collective molecular pathways involved in biotransformation of nutrients to produce tissues (dhatus), and energy. Agni is also responsible for catabolic activities. There are 13 types of Agni described in Ayurveda.

Agni-mandya: Refers to inappropriate functioning of Agni which eventually affects the digestion, absorption and assimilation of nutrients in the body.

Ahara: Food, drinks and other dietary substances consumed by the living organisms.

Ahara Rasa: The primary nutritive essence, generated after the digestion of food and drinks, that can be absorbed and ideally assimilated into the body. It supports seven tissue systems (dhatus- further explained) of the body.

Ama: It is used to denote the products and process of incomplete or inappropriate biotransformation of the nutrients at gastrointestinal tract and tissue levels. It also includes impaired products such as immunogenic precursors or aberrant metabolic intermediates of cellular biochemical transformation that eventually alter the normal biological functions. Ama formation is happening when the Agni functions are not proper. Ama is eliminated and further, its formation is prevented by modulating Agni through various methods including the medicinal herbs and formulations.

Dhatu (seven types): From Ayurveda epistemology, Dhatu denotes the fundamental building blocks of the body (roughly equivalent to the tissues in modern biology). There are seven Dhatus sequentially named as Rasa (∼ nutrient rich chyme), Rakta (∼blood), Mamsa (∼muscle), Meda (∼ adipose tissue), Asthi (∼ skeletal tissue), Majja (∼ bone marrow) and Sukra (∼ reproductive tissue). Rasa Dhatu is the first derivation from ingested food and each of the subsequent Dhatu derives from the previous one in the sequence. However, each dhatu can be directly derived from Ahara rasa.

Dhatu Agni: Seven Agni are involved in the biotransformation of each Dhatu from its respective precursors. For e.g., The Rasa Dhatu Agni is responsible for conversion of Ahara rasa into Rasa Dhatu.

Dravyaguna: The Ayurvedic discipline that studies medicinal substances and explains their therapeutic actions based on their properties, actions, and interactions with the body.

Prakriti: Describes an individual’s inherent pattern of physical, physiological, and psychological traits, considered as a stable baseline that helps explain why people differ in metabolism, resilience, and health risks. Prakriti is defined as the independent or combined dominance of either Vata, Pitta or Kapha Dosha.

Rasapanchaka: The Ayurvedic framework describing drug action through five determinants referred as rasa (taste), guna (qualities), virya (potency), vipaka (post-digestive effect), and prabhava (specific action).

Srotodushti: Refers to the dysfunctions or disturbances in the body’s internal transport and communication pathways, known as srotas, which are responsible for the movement of nutrients, wastes, fluids, and signals throughout the body.

Vikriti: Denotes the “current state of imbalance” in a person’s body and mind, which reflects how lifestyle, diet, stress, environment, illness, or aging have temporarily disturbed the physiological homeostasis. Vikriti guides personalized corrective measures such as dietary changes, lifestyle adjustments, or treatments to restore health.