What question did this study set out to answer?

To explore the complex mechanisms and safety profile of paracetamol, integrating molecular pharmacology and nanotherapeutic approaches.

May 14, 2026Open Access

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Re-Engineering Paracetamol (Acetaminophen) in the 21st Century: Molecular Pharmacology, Systems Toxicology, and Nano-Therapeutic Innovations

Key Points

To explore the complex mechanisms and safety profile of paracetamol, integrating molecular pharmacology and nanotherapeutic approaches.
Comprehensive review of the pharmacological landscape of paracetamol, focusing on its hepatic metabolism and toxicity mechanisms.
Evaluation of nano-enabled drug delivery systems like polymeric nanoparticles and lipid-based carriers.
Examination of epidemiological evidence regarding chronic exposure and clinical controversies.
Paracetamol exhibits multifaceted pharmacodynamics, not solely reliant on COX inhibition.
Hepatotoxicity is linked to NAPQI formation and subsequent oxidative stress and mitochondrial dysfunction.
Nanomedicine shows promise in enhancing the therapeutic index and reducing toxicity in paracetamol use.

Abstract

Paracetamol (acetaminophen) continues to occupy a central position in global therapeutics as a first-line analgesic and antipyretic agent, yet its mechanistic intricacies and safety profile remain subjects of sustained scientific interrogation. Traditionally perceived as a peripherally weak cyclooxygenase (COX) inhibitor, contemporary evidence has repositioned paracetamol as a centrally acting drug with multifaceted pharmacodynamics involving serotonergic modulation, endocannabinoid signaling, transient receptor potential vanilloid 1 (TRPV1) activation, and redox-sensitive pathways. This review provides a comprehensive and technically rigorous synthesis of paracetamol’s advanced pharmacological landscape, integrating classical biochemical pathways with emerging insights from systems pharmacology and nanomedicine. A critical focus is placed on its hepatic metabolism, wherein a fraction undergoes cytochrome P450-mediated bioactivation to N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive electrophile responsible for dose-dependent hepatotoxicity. The pathogenesis of paracetamol-induced liver injury is explored through mitochondrial dysfunction, oxidative stress amplification, sterile inflammation, and immune-mediated signaling cascades. Furthermore, recent advances in nano-enabled drug delivery systems—including polymeric nanoparticles, lipid-based carriers, and smart hydrogels—are evaluated for their potential to enhance therapeutic index, optimize pharmacokinetics, and mitigate toxicity. The review also critically examines epidemiological evidence regarding chronic exposure risks, regulatory frameworks, and clinical controversies across diverse populations. By bridging molecular pharmacology with translational and technological innovations, this article aims to redefine the therapeutic narrative of paracetamol, providing a future-oriented perspective consistent with Scopus-indexed publication standards.

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Re-Engineering Paracetamol (Acetaminophen) in the 21st Century: Molecular Pharmacology, Systems Toxicology, and Nano-Therapeutic Innovations

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