Two highly oxygenated pentacyclic polyketides with two new carbon skeletons, trichopsistide A (1) and trichopsistide B (2), were isolated from the plant endophyte Trichoderma koningiopsis WZ-196 derived from the leaf of Rubia podantha Diels. The structures of these polyketides with full configurations were determined by comprehensive spectroscopic analysis, computer-assisted structure elucidation software, computational calculation, and X-ray crystal diffraction. Among them, 1 represented the first example of an unprecedented 5/6/6/6/5 pentacyclic ketal-containing polyketide pyridine alkaloid, and 2 possessed a novel 6/6/6/6/5 pentacyclic ketal-containing polyketide scaffold fused with an alpha-pyrone. The plausible biosynthetic route for 1 and 2 was also proposed. Moreover, biological activity assays showed that 1 and 2 possessed inhibitory effects on the NF-kappaB signaling pathway with IC(50) values of 14.77 and 8.58 muM, respectively. Furthermore, 1 and 2 could also inhibit the expression of IkappaBalpha and p65 phosphorylation, decrease the expression of MCP-1, E-selectin, and IL-8 at the mRNA level, and inhibit the TNF-alpha-induced nuclear translocation of p65.