**1. Introduction**

Filamentous fungi are rich producers of bioactive secondary metabolites, some of which either have been developed as commercial drugs to save lives or are carcinogenic or neurotoxic mycotoxins that threaten human health [1]. The production of these compounds has long been considered to be dispensable for fungal biology since the disruption of the biosynthetic gene clusters (BGCs) could barely, if at all, impair fungal growth and development under experimental conditions [2]. However, many studies have shown that the small molecules produced by fungi play essential roles in fungus–environment interactions [3,4]. For example, metabolites with antibiotic and antifungal activities are used by the producing fungi to outcompete other microbes [5,6]. The phytotoxins produced by plant pathogens are required in mediating fungus–plant interactions [7], and insecticidal toxins biosynthesized by insect pathogens facilitate fungal infection of insect hosts [8,9]. In addition, the mycotoxins produced by plant pathogens or endophytes can frequently result in toxic effects at different levels in herbivorous animals [10], which has been considered as a strategy employed by plants against grazers [11]. Thus, small molecules produced by fungi are of biological importance to producers and beyond.

In nature, there are more than 1000 species of fungi that can infect and kill insects, most of which are ascomycete entomopathogenic fungi [12]. In particular, three families of Hypocrealean fungi, i.e., Cordycipitaceae, Ophiocordycipitaceae, and Clavicipitaceae, contain species that have been used either for biocontrol of insect pests or as Traditional Chinese Medicine (TCM) in Asian countries and beyond [13,14]. For example, the species of *Ophiocordyceps sinensis*, *Cordyceps militaris*, and *C. cicadae* (syn. *Isaria cicadae*) have been used as TCM with recorded antibiotic, anti-inflammatory, anti-aging, anti-cancer, anti-proliferative, anti-metastatic, anti-fatigue, and immunomodulatory activities or effects (Table 1) for a long time in history [15,16]. On the other hand, similar to other traditional herbs, the safety of consuming these fungi has long been a concern [16]. A plethora of bioactive metabolites have been identified from Hypocrealean entomopathogens [14,17,18], including those which have been developed as commercial drugs such as the immunosuppressant drug cyclosporin A, a cyclodepsipeptide isolated from the Ophiocordycipitaceae fungus *Tolypocladium inflatum* [6] and the anti-leukemia drug pentostatin, first isolated from *Streptomyces*, found in *C. militaris* [19]. Apart from the medicinal or beneficial effects reported for the chemicals identified from *Cordyceps* fungi, side effects of cytotoxicity and or neurological toxicity have also been reported for these compounds (Table 1). Anecdotal records of nausea, diarrhea and even excessive post-extraction bleeding have been reported after daily consumption of *Cordyceps* fruiting bodies or related products [20,21]. Thus, in-depth safety evaluation is still required before consuming these fungi.


**Table 1.** Summary of the reported bioactivity and toxicity of the compounds identified from *Cordyceps* fungi.


**Table 1.** *Cont.*

*Cordyceps* fungi are being mass produced for harvesting the fruiting bodies for food and health additives while the byproducts (largely culture substrates) of mass production are then mostly used as animal feed [22]. To alleviate the safety concerns for both purposes, this paper reviews the production and biological activity/toxicity of known metabolites identified from *Cordyceps* fungi and unknown metabolites deduced from the conserved biosynthetic gene clusters (BGCs) by comparative analysis with those BGCs involved in producing known mycotoxins based on the obtained genome information of these fungi [23–25]. The content of literature reviews conducted in the paper may benefit the future exploration and safety assessment of *Cordyceps* fungi and their related byproducts used for food, traditional medicine or animal feed.
