Ganoderma lucidum (Lingzhi), a traditional medicinal mushroom, is renowned for its immunomodulatory, anti-inflammatory, and antioxidant properties, primarily attributed to its bioactive components such as polysaccharides and triterpenoids. This review focuses on the mechanisms by which Ganoderma lucidum modulates immune responses, particularly in the context of gut–liver–brain axis disorders. Polysaccharides enhance immune function by activating macrophages, natural killer cells, and T cells, thereby promoting phagocytosis and cytokine production. Triterpenoids contribute through anti-inflammatory and antioxidant activities, inhibiting inflammatory mediators and protecting tissues from damage. Ganoderma lucidum also influences immune regulation via key signaling pathways, including NF-κB and MAPK, and supports immune tolerance, potentially reducing the risk of autoimmune diseases. Additionally, it modulates gut microbiota, which further impacts systemic immunity. Importantly, polysaccharides and triterpenoids demonstrate promising clinical application prospects in metabolic diseases, inflammatory conditions, neurodegenerative disorders, and cancer immunotherapy, attributed to their multi-target immunomodulatory activities and prebiotic properties. Despite promising applications in treating metabolic, inflammatory, and neurodegenerative diseases, further research is needed to fully elucidate the molecular mechanisms and potential of Ganoderma lucidum in precision medicine. This comprehensive analysis underscores the value of Ganoderma lucidum as a multifaceted immunomodulatory agent.

Lysine acetyltransferase 8 (KAT8) is a member of the MYST family of histone acetyltransferases. It catalyzes the acetylation of histone H4 at lysine 16 (H4K16ac) and non-histone proteins. Abnormal upregulation or downregulation of KAT8 and its associated H4K16ac have been observed in malignant tumors, suggesting its close association with tumorigenesis and progression. Characterized by structural diversity and multi-target mechanisms, natural agents have been increasingly shown to possess significant antitumor activity. This review focuses on KAT8, summarizing its molecular mechanisms in regulating tumor development by catalyzing substrate protein acetylation, which impacts tumor cell proliferation, cell cycle regulation, apoptosis, DNA damage repair, and autophagy. It also systematically discusses the pharmacological activities and molecular mechanisms of small-molecule agents that target KAT8 to inhibit tumor proliferation, including natural compounds, synthetic drugs, and non-coding RNAs.